JP2005519932A - Nicotinamide derivatives useful as p38 inhibitors - Google Patents

Abstract

The compounds of formula (I) are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or cytokines produced by the activity of p38.

Description

  The present invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors for the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase. Regarding use.

  The present inventors have found a novel group of compounds that are inhibitors of p38 kinase.

According to the present invention, a compound of the following formula (I) is provided.

Where
R ¹ is hydrogen, C _1-6 alkoxy, halogen and optionally substituted by not more than three groups selected from hydroxy C _1-6 alkyl, C _2-6 alkenyl, 1 or more C _1-6 C _3-7 cycloalkyl optionally substituted by an alkyl group, phenyl optionally substituted by up to 3 groups selected from R ⁵ and R ⁶ , and 3 selected from R ⁵ and R ⁶ Selected from heteroaryl optionally substituted by not more than one group;
R ² is selected from hydrogen, C _1-6 alkyl and — (CH ₂ ) _q —C _3-7 cycloalkyl, optionally substituted by one or more C _1-6 alkyl groups;
Alternatively, (CH ₂ ) _m R ¹ and R ² together with the nitrogen atom to which they are bonded may be substituted with 3 or less C _1-6 alkyl group and may be substituted with 4 to 6 membered complex. Forming a ring;
R ³ is chloro or methyl;
R ⁴ is a group —NH—CO—R ⁷ or —CO—NH— (CH ₂ ) _q —R ⁸ ;
R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , —SO ₂ NHR ⁹ , — (CH ₂ ) _s NHSO ₂ R ¹⁰ , halogen, CN, OH, — (CH ₂ ) _s NR ¹¹ R ¹² and trifluoromethyl;
R ⁶ is selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, trifluoromethyl and — (CH ₂ ) _s NR ¹¹ R ¹² ;
R ⁷ is hydrogen, C _1-6 alkyl, _optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, trifluoromethyl, R ¹³ and / or or optionally substituted by R ¹⁴ - (CH _{2) r} heteroaryl, and optionally substituted by R ¹³ and / or R ¹⁴ - (CH ₂₎ selected from the _r phenyl;
R ⁸ is substituted by hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl optionally substituted by one or more C _1-6 alkyl groups, CONHR ⁹ , R ¹³ and / or R ¹⁴ Selected from good phenyl and heteroaryl optionally substituted by R ¹³ and / or R ¹⁴ ;
R ⁹ and R ¹⁰ are each independently selected from hydrogen and C _1-6 alkyl;
Alternatively, R ⁹ and R ¹⁰ may have one further heteroatom selected from oxygen, sulfur and NR ¹⁵ together with the nitrogen atom to which they are attached. And the ring may be substituted by not more than 2 C _1-6 alkyl groups;
R ¹¹ is selected from hydrogen, C _1-6 alkyl and — (CH ₂ ) _q —C _3-7 cycloalkyl, optionally substituted by one or more C _1-6 alkyl groups;
R ¹² is selected from hydrogen and C _1-6 alkyl;
Alternatively, R ¹¹ and R ¹² together with the nitrogen atom to which they are attached may have one further heteroatom selected from oxygen, sulfur and NR ¹⁵ 5 or 6 Forming a heterocycle of members;
R ¹³ is C _1-6 alkyl, C _1-6 alkoxy, optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ^10, -NHCOR ^10, _{halogen, CN, - (CH 2)} s NR 11 R 12, trifluoromethyl, optionally substituted by one or more optionally substituted by R ¹⁴ groups phenyl and one or more, R ¹⁴ group Selected from optionally heteroaryl;
R ¹⁴ is selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, trifluoromethyl and —NR ¹¹ R ¹² ;
R ¹⁵ is selected from hydrogen and methyl;
X and Y are each independently selected from hydrogen, methyl and halogen;
Z is a halogen;
m is selected from 0, 1, 2, 3 and 4 and each carbon atom of the resulting carbon chain may be substituted by up to 2 groups independently selected from C _1-6 alkyl and halogen;
n is selected from 0, 1 and 2;
q is selected from 0, 1 and 2;
r is selected from 0 and 1;
s is selected from 0, 1, 2 and 3.

According to another embodiment of the present invention, a compound of the following formula (IA) is provided.

Wherein R ¹ , R ² , R ³ , R ⁴ and m are as defined above.

According to one embodiment of the invention, R ¹ is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, R ⁵ and / or phenyl optionally substituted by R ⁶ , and R ⁵ and / or Selected from heteroaryl optionally substituted by R ⁶ ; R ² is selected from hydrogen, C _1-6 alkyl and — (CH ₂ ) _q —C _3-7 cycloalkyl.

In a preferred embodiment, R ¹ is substituted by no more than 3 groups selected from C _1-6 alkoxy, in particular C _1-4 alkoxy groups such as methoxy or t-butoxy, halogen, in particular fluorine, and hydroxy. C _1-6 alkyl which may be _substituted , for example methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl-1-methyl-propyl N-butyl, isobutyl, 3-methylbutyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1-methylpentyl; C _2-6 alkenyl, such as 3- C _4-6 alkenyl such as methylbut-2-enyl or 1,1-dimethylbut-2-enyl; C _3-7 cycloalkyl _optionally substituted by one or more C _1-6 alkyl groups, for example methyl Or even one such as ethyl Ku is two C _1-4 good cyclopropyl optionally substituted by an alkyl group, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl; substituted by not more than three groups selected from R ⁵ and R ⁶ Optionally phenyl, for example up to 3 substituents, for example C _1-4 alkyl in any position of the ring, in particular methyl, C _1-4 alkoxy, in particular methoxy, halogen, in particular fluorine or chlorine, Phenyl optionally substituted by one or two substituents such as trifluoromethyl, — (CH ₂ ) _s NR ¹¹ R ¹² or — (CH ₂ ) _s NHSO ₂ R ¹⁰ ; from R ⁵ and R ⁶ 3 or less good heteroaryl optionally substituted by a group selected, for example, one or two heteroaryl optionally substituted with a substituent, in particular C _1-4 alkyl, in particular Furyl which may be substituted by methyl, is selected from 5-membered heteroaryl such as thienyl or thiazolyl. In particularly preferred embodiments, R ¹ is C _1-6 alkyl, such as ethyl, n-propyl, isopropyl, 1-methylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-butyl, isobutyl, 3 -C _2-5 alkyl such as methylbutyl or 2-pentyl.

R ¹ is In another preferred embodiment, C _3-7 cycloalkyl, R ⁵ and / or phenyl optionally substituted by R ^6, and R ⁵ and / or heteroaryl optionally substituted by R ⁶ Selected from. In a more preferred embodiment R ¹ is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular C _3-6 cycloalkyl such as cyclopropyl, and phenyl optionally substituted by R ⁵ and / or R ⁶ . The The phenyl may be substituted by one or two substituents at any position on the phenyl ring. Preferred substituents for said phenyl include C _1-4 alkoxy, especially methoxy, — (CH ₂ ) _s NR ¹¹ R ¹² and — (CH ₂ ) _s NHSO ₂ R ¹⁰ .

In another preferred embodiment, R ¹ is represented by C _1-6 alkyl such as n-propyl, 1-methylpropyl, isobutyl, 3-methylbutyl or 2,2-dimethylpropyl, and one or more C _1-6 alkyl groups. It is selected from optionally substituted C _3-7 cycloalkyl, for example cyclopropyl optionally substituted by one or two methyl groups.

In a further preferred embodiment R ¹ is substituted by 3 or less groups selected from C _1-6 alkoxy, in particular C _1-4 alkoxy, such as methoxy or t-butoxy, halogen, in particular fluorine and hydroxy. C _1-6 alkyl, eg methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, 1-ethyl-1-methyl-propyl, n-butyl, isobutyl, 1,1-dimethylbutyl 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2-pentyl or 1-methylpentyl; C _2-6 alkenyl, such as 3-methylbut-2-enyl or 1,1-dimethylbut-2-enyl C _3-6 alkenyl; C _3-7 cycloalkyl _optionally substituted by one or more C _1-6 alkyl groups, eg cyclopropyl, cyclopentyl optionally substituted by one or two ethyl groups Also Is cyclohexyl; phenyl optionally substituted by no more than 3 groups selected from R ⁵ and R ⁶ , eg C _1-4 alkyl in any position of the ring, in particular methyl, C _1-4 alkoxy Phenyl, optionally substituted by up to 3 substituents such as methoxy, halogen, in particular fluorine or chlorine and trifluoromethyl; substituted by up to 3 groups selected from R ⁵ and R ⁶ Optionally selected from heteroaryl, in particular C _1-4 alkyl, in particular from 5-membered heteroaryl such as furyl, thienyl or thiazolyl optionally substituted by methyl.

In a preferred embodiment R ² is hydrogen; C _1-4 alkyl, especially methyl, ethyl, isopropyl or isobutyl; and — (CH ₂ ) _q —C _3-6 cycloalkyl, especially cyclopropyl, —CH ₂ — Selected from cyclopentyl, — (CH ₂ ) ₂ -cyclopentyl or cyclohexyl.

In another preferred embodiment, R ² is selected from hydrogen, C _1-4 alkyl and —CH ₂ -cyclopropyl. More preferably R ² is hydrogen.

In a further preferred embodiment, (CH ₂ ) _m R ¹ and R ² together with the nitrogen atom to which they are attached may be substituted by 3 or less C _1-6 alkyl groups. It forms a 6-membered heterocycle, in particular an azetidinyl, pyrrolidinyl or piperidinyl ring which may be substituted by one or two methyl, ethyl or propyl groups.

In a preferred embodiment, R ³ is methyl.

In a preferred embodiment, R ⁴ is a group —CO—NH— (CH ₂ ) _q —R ⁸ .

In one embodiment of the present invention, R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , —SO _2. Selected from NHR ⁹ , — (CH ₂ ) _s NHSO ₂ R ¹⁰ , halogen, CN, OH, — (CH ₂ ) _s NR ¹¹ R ¹² and trifluoromethyl.

In a preferred embodiment R ⁵ is C _1-4 alkyl, especially methyl; C _1-4 alkoxy, especially methoxy; — (CH ₂ ) _s NHSO ₂ R ¹⁰ ; halogen, especially chlorine or fluorine; — (CH ₂ ) selected from _s NR ¹¹ R ¹² ; and trifluoromethyl.

In another preferred embodiment, R ⁵ is selected from C _1-4 alkoxy, in particular methoxy, — (CH ₂ ) _s NR ¹¹ R ¹² and — (CH ₂ ) _s NHSO ₂ R ¹⁰ .

In a further preferred embodiment R ⁵ is selected from C _1-4 alkyl, in particular methyl; C _1-4 alkoxy, in particular methoxy; halogen, in particular chlorine or fluorine; and trifluoromethyl.

In a preferred embodiment R ⁶ is selected from C _1-4 alkyl, especially methyl, ethyl or propyl; C _1-4 alkoxy, especially methoxy; halogen, especially chlorine or fluorine; and trifluoromethyl.

In a further preferred embodiment R ⁶ is C _1-4 alkoxy, especially methoxy.

In one embodiment of the invention, R ⁷ may be substituted by hydrogen, C _1-6 alkyl, — (CH ₂ ) _q —C _3-7 cycloalkyl, trifluoromethyl, R ¹³ and / or R ¹⁴ . Selected from good — (CH ₂ ) _r heteroaryl and — (CH ₂ ) _r phenyl optionally substituted by R ¹³ and / or R ¹⁴ .

In a preferred embodiment, R ⁷ is C _1-6 alkyl, — (CH ₂ ) _q —C _3-7 cycloalkyl, trifluoromethyl, R ¹³ and / or R ¹⁴ optionally substituted — (CH ₂ ) _r heteroaryl, and C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , halogen, CN, trifluoromethyl, It is selected from (CH _{2) r} phenyl - optionally substituted by heteroaryl optionally substituted by optionally substituted phenyl and / or one or more R ¹⁴ groups by one or more R ¹⁴ groups . In another preferred embodiment, R ⁷ is optionally substituted by C _1-4 alkyl, — (CH ₂ ) _q —C _3-6 cycloalkyl, trifluoromethyl, R ¹³ and / or R ¹⁴ — ( CH ₂ ) _r heteroaryl, as well as C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , halogen, CN, trifluoro selected from (CH _{2) r} phenyl - methyl, which may be substituted by heteroaryl optionally substituted by optionally substituted phenyl and / or one or more R ¹⁴ groups by one or more R ¹⁴ groups Is done. In a more preferred embodiment R ⁷ represents at least one heteroatom selected from — (CH ₂ ) _r heteroaryl, in particular oxygen, nitrogen and sulfur, optionally substituted by R ¹³ and / or R ¹⁴ . It is pyridinyl optionally substituted by 5 or 6 membered heteroaryl having, for example, —NR ¹¹ R ¹² , furyl or thiophenyl.

In one embodiment of the invention, R ⁸ is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, CONHR ⁹ , phenyl optionally substituted by R ¹³ and / or R ¹⁴ , and R ¹³ and / or Or selected from heteroaryl optionally substituted by R ¹⁴ .

In preferred embodiments, R ⁸ is C _3-7 cycloalkyl, heteroaryl optionally substituted by CONHR ⁹ , R ¹³ and / or R ¹⁴ , and C _1-6 alkyl, C _1-6 alkoxy, — ( CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R ¹⁴ groups and / or one or more Selected from phenyl optionally substituted by heteroaryl optionally substituted by R ¹⁴ group. In another preferred embodiment, R ⁸ is C _3-7 cycloalkyl, heteroaryl optionally substituted by R ¹³ and / or R ¹⁴ , and C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q -C _3-7 cycloalkyl, -CONR ⁹ R ¹⁰ , -NHCOR ¹⁰ , halogen, CN, trifluoromethyl, phenyl optionally substituted by one or more R ¹⁴ groups and / or one or more R Selected from phenyl optionally substituted by heteroaryl optionally substituted by ¹⁴ groups. In a more preferred embodiment R ⁸ is C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl, heteroaryl, in particular optionally substituted by R ¹³ and / or R ¹⁴ Selected from 5- or 6-membered heteroaryl having at least one heteroatom selected from nitrogen and sulfur, for example thiazolyl or thiadiazolyl, and phenyl optionally substituted by heteroaryl. In a particularly preferred embodiment R ⁸ is selected from C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in particular cyclopropyl.

In a preferred embodiment, R ⁹ is selected from hydrogen and C _1-4 alkyl.

In a preferred embodiment, R ¹⁰ is selected from hydrogen and C _1-4 alkyl, especially methyl.

In one embodiment, R ¹¹ is selected from — (CH ₂ ) _q —C _3-7 cycloalkyl, optionally substituted by hydrogen, C _1-6 alkyl and C _1-6 alkyl.

In preferred embodiments, R ¹¹ and R ¹² together with the nitrogen atom to which they are attached, may further have one additional heteroatom NR ¹⁵ , a 5- or 6-membered heterocycle Is forming.

In one embodiment of the invention, R ¹³ is C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , halogen, CN _{, - (CH 2) s NR} 11 R 12, trifluoromethyl, is selected from heteroaryl optionally substituted by optionally substituted phenyl and 1 or more R ¹⁴ groups by one or more R ¹⁴ groups .

In a preferred embodiment R ¹³ is substituted by C _1-4 alkyl, especially methyl, C _1-4 alkoxy, especially methoxy, halogen, — (CH ₂ ) _s NR ¹¹ R ¹² , one or more R ¹⁴ groups. Selected from optionally substituted phenyl and heteroaryl optionally substituted by one or more R ¹⁴ groups. In a more preferred embodiment, R ¹³ is — (CH ₂ ) _s NR ¹¹ R ¹² and heteroaryl optionally substituted by one or more R ¹⁴ groups, in particular 5 or 6 having at least one nitrogen atom. Selected from membered heteroaryl, eg pyridyl.

In a preferred embodiment, R ¹⁴ is selected from C _1-4 alkyl, especially methyl, C _1-4 alkoxy, especially methoxy, and —NR ¹¹ R ¹² .

In a preferred embodiment, R ¹⁵ is methyl.

  In a preferred embodiment, X and Y are each independently selected from hydrogen, chlorine and fluorine. In a further preferred embodiment, X is fluorine. In another preferred embodiment, Y is hydrogen.

  In a preferred embodiment, Z is fluorine.

In one embodiment of the present invention, m is selected from 0, 1, 2, 3 and 4. In another embodiment of the invention, m is selected from 0, 1, 2, 3 and 4 and each carbon atom of the resulting carbon chain is substituted by no more than 2 groups independently selected from C _1-6 alkyl. May be.

  In preferred embodiments, m is selected from 0, 1, 2, and 3. In a further preferred embodiment m is selected from 0, 1 and 2, in particular from 0 and 1. When the m carbon chain is substituted, the substituent is preferably one or two methyl groups or a fluorine atom. In one embodiment, the substituent is preferably one or two methyl groups. In another embodiment, the substituent is preferably 1 or 2 fluorine atoms.

  In a preferred embodiment, n is selected from 0 and 1. In particular, n is 0.

  In a preferred embodiment, q is selected from 0 and 1. In particular, q is 0.

  In a preferred embodiment, r is 0.

  In preferred embodiments, s is selected from 0 and 1.

  It should be understood that the present invention covers all combinations of the specific groups and preferred groups described above.

Specific compounds according to the invention include those described in the examples. Specific examples that can be mentioned include:
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N-cyclopropylmethyl-nicotinamide;
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N- (1-cyclopropylethyl) -nicotinamide;
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N- (2,2-dimethylpropyl) -nicotinamide;
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N- (2-methylpropyl) -nicotinamide; and
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N- (1-methylpropyl) -nicotinamide.

More specific examples that can be mentioned include:
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N-cyclobutylmethyl-nicotinamide;
6- (5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl) -N-cyclobutyl-nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,4,5-trifluorobenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,5-difluorobenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (3,4-difluorobenzyl) nicotinamide;
N- (3-chlorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
N- (4-chlorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
N- (3-chloro-2-fluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
N- (2-chloro-3,6-difluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,3-difluoro-4-methylbenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,3,5-trifluorobenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (3-fluoro-4-methylbenzyl) nicotinamide;
N- (5-chloro-2-fluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
N- (2-chlorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (4-fluorobenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,3,4-trifluorobenzyl) nicotinamide;
N-benzyl-6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- [3- (trifluoromethyl) benzyl] nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (1,1-dimethylbutyl) nicotinamide;
N- (4-chloro-2-fluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- [4- (trifluoromethyl) benzyl] nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N-[(5-methyl-2-furyl) methyl] nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2,3-difluorobenzyl) nicotinamide;
N- (3-chloro-4-fluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (4-methylbenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N-[(3-methylthien-2-yl) methyl] nicotinamide;
N- (3-chloro-2,6-difluorobenzyl) -6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (1-ethyl-1-methylpropyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (2-fluorobenzyl) nicotinamide;
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (tert-pentyl) nicotinamide; and
6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} -N- (3-methylbenzyl) nicotinamide.

As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain having the specified number of carbon atoms. For example, C _1-6 alkyl means a straight or branched alkyl having at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and t-butyl. It is not a thing. A C _1-4 alkyl group is preferred, for example methyl, ethyl, isopropyl or t-butyl. The alkyl group may be substituted with one or more fluorine atoms, for example, trifluoromethyl.

The term “alkenyl” as used herein refers to a straight or branched hydrocarbon chain having the specified number of carbon atoms and having at least one double bond. For example, C _2-6 alkenyl means a straight or branched alkenyl having at least 2, at most 6, carbon atoms and having at least one double bond. Examples of “alkenyl” as used herein include, but are not limited to, ethenyl, propenyl, 3-methylbut-2-enyl, and 1,1-dimethylbut-2-enyl. is not.

As used herein, the term “alkoxy” refers to a straight or branched alkoxy group, such as methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylpropoxy. Refers to -1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy. A C _1-4 alkoxy group is preferred, for example methoxy or ethoxy.

The term “cycloalkyl” as used herein refers to a non-aromatic hydrocarbon ring having a specified number of carbon atoms that may have no more than one double bond. For example, C _3-7 cycloalkyl means a non-aromatic ring having at least 3, and at most 7, ring carbon atoms. Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C _3-6 cycloalkyl group is preferred, for example cyclopropyl, cyclopentyl or cyclohexyl. The cycloalkyl group may be substituted by one or more C _1-6 alkyl groups, for example, one or two methyl groups. In one embodiment, the cycloalkyl group has no more than 4 C _1-6 alkyl groups, for example 1 or 2 C _1-6 alkyl groups, especially 1 or 2 C ₁ such as methyl or ethyl. _May be substituted by a _-4 alkyl group.

As used herein, the terms “heteroaryl ring” and “heteroaryl” are monocyclic and 5-membered to having at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Refers to a 7-membered unsaturated hydrocarbon ring. Preferably the heteroaryl ring has 5 or 6 ring atoms. Examples of heteroaryl rings include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. It is not limited. The ring may be substituted with one or more substituents independently selected from C _1-6 alkyl and oxy.

The term “heterocycle” or “heterocyclic” as used herein is monocyclic and 3-7 membered having at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Of saturated hydrocarbon rings. Preferably the heterocycle has 5 or 6 ring atoms. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl and thiomorpholino. The ring may be substituted with one or more substituents independently selected from C _1-6 alkyl and oxy.

  The term “halogen” or “halo” as used herein refers to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. Particularly preferred halogen is fluorine or chlorine.

  As used herein, “may be” means that the event described may or may not be present and includes both events that occur and events that do not occur.

  As used herein, the term “substituted” refers to substitution with a specified substituent or multiple substituents, and multiple substitutions are possible unless otherwise specified.

  As used herein, the term “solvate” can vary in the stoichiometric amount formed by the solute (in the present invention, the compound of formula (I) or a salt thereof) and the solvent. Refers to a complex. Such solvents for the present invention cannot interfere with the physiological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Any such solvates are within the scope of the present invention.

  Certain compounds of formula (I) may exist in stereoisomeric forms (eg it may have one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also includes the individual isomers of the compounds represented by formula (I) as mixtures with isomers in which one or more chiral centers are inverted. Similarly, it should be understood that compounds of formula (I) may exist in tautomeric forms other than those shown in the above formulas and are within the scope of the present invention.

  Salts of the compounds of the present invention are also encompassed within the scope of the present invention, and can include, for example, acid addition salts resulting from the reaction of a basic nitrogen atom present in a compound of formula (I) with an acid.

  Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Typical salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, acid tartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride , Clavulanate, Citrate, Dihydrochloride, Edetate, Edicylate, Estolate, Esylate, Fumarate, Gluceptonate, Gluconate, Glutamate , Glycolylarsanylate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate , Maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, mucoate, napsylate, nitrate, N-methyl group Kamin, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium salt, salicylate, sodium salt, stearate, There are salts such as basic acetates, succinates, tannates, tartrate, teocrate, tosylate, triethiodide, trimethylammonium salt and valerate. Other pharmaceutically unacceptable salts may be useful in the manufacture of the compounds of the present invention and they form yet another aspect of the present invention.

  The compounds of this invention can be made by a variety of methods, including standard chemistry. Unless otherwise noted, variables defined so far still have their previously defined meanings. Examples of general synthetic methods are shown below, and specific compounds of the invention are prepared in the examples.

The compound of the formula (I) is a compound of the following formula (II):

Wherein R ¹ , R ² , Z, m and n are as defined above and W is a halogen, in particular bromine or chlorine, and a compound of the following formula (III):

(Wherein R ³ , R ⁴ , X and Y are as defined above) can be prepared by reacting in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium.

The compound of formula (II) is a corresponding acid compound of formula (IV):

(Wherein Z, W and n are as defined above), the acid is converted to an activated form of the acid, eg acid chloride (eg by treatment with thionyl chloride) The activated acid thus formed is converted to an amine compound of the following formula (V) under amide-forming conditions:

(Wherein R ¹ , R ² and m are as defined above) can be easily produced.

  Suitable amide formation conditions are known in the art and an acid of formula (IV) or an activated form thereof, for example an acetone or methylene chloride solution, is treated with an amine of formula (V) in the presence of sodium carbonate. There are things.

The compound of the formula (III) is a compound of the following formula (VI):

Wherein R ³ , R ⁴ , X and Y are as defined above and hal is halogen, in particular iodine, in a solvent such as DMF bis (pinacolato) diboron, PdCl ₂ dppf and It can be produced by reacting with potassium acetate.

Alternatively, when R ⁴ is —CO—NH— (CH ₂ ) _q —R ⁸ , the compound of formula (III) is an acid compound of formula (VII):

(Wherein R ³ , hal, X and Y are as defined above) are reacted with bis (pinacolato) diboron, PdCl ₂ dppf and potassium acetate in a solvent such as DMF and then defined above. Can be prepared by forming an amide by reacting with an amine compound of formula (V).

The compound of formula (I) is a compound of the following formula (VIII):

By reacting a compound of formula (III) as defined above and then reacting the acid so formed with an amine of formula (V) as defined above under amide-forming conditions. You can also.

Further, the compound of formula (I) is a compound of formula (II) as defined above:

(Wherein R ³ , R ⁴ , X and Y are as defined above) and can be produced in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium.

For example, one common method for preparing compounds of formula (I) involves the reaction shown in Scheme 1 below.

Scheme 1
i. R ⁷ CO ₂ H, HATU, DIPEA, DMF;
ii. Bis (pinacolato) diboron, PdCl ₂ dppf, KOAc, DMF;
iii. SOCl ₂ ；
iv. R ¹ (CH ₂ ) _m R ² NH, Na ₂ CO ₃ , acetone;
v. Na ₂ CO ₃ , tetrakis (triphenylphosphine) palladium, propan-2-ol.

For example, another common method for preparing compounds of formula (I) involves the reaction shown in Scheme 2 below.

Scheme 2
i. SOCl ₂ ；
ii. R ⁸ (CH ₂ ) _q NH ₂ , Na ₂ CO ₃ , acetone;
iii. Bis (pinacolato) diboron, PdCl ₂ dppf, KOAc, DMF;
iv. SOCl ₂ ；
v. R ¹ (CH ₂ ) _m R ² NH, Na ₂ CO ₃ , acetone;
vi. Na ₂ CO ₃ , tetrakis (triphenylphosphine) palladium, propan-2-ol.

For example, another common method for preparing compounds of formula (I) involves the reaction shown in Scheme 3 below.

Scheme 3
i. Bis (pinacolato) diboron, PdCl ₂ dppf, KOAc, DMF;
ii. R ⁸ (CH ₂ ) _q NH ₂ , HATU, DIPEA, DMF;
iii. SOCl ₂ ；
iv. R ¹ (CH ₂ ) _m R ² NH, Na ₂ CO ₃ , DCM;
v. Na ₂ CO ₃ , tetrakis (triphenylphosphine) palladium, propan-2-ol.

For example, another common method for preparing compounds of formula (I) involves the reaction shown in Scheme 4 below.

Scheme 4
i. NaHCO ₃ , tetrakis (triphenylphosphine) palladium, propan-2-ol;
ii. R ¹ (CH ₂ ) _m R ² NH, HATU, DIPEA, DMF.

For example, yet another common method for preparing compounds of formula (I) involves the reaction shown in Scheme 5 below.

Scheme 5
i. SOCl ₂ ；
ii. R ⁸ (CH ₂ ) _q NH ₂ , Na ₂ CO ₃ , DCM;
iii. NaH, n-BuLi, THF, (iPrO) ₃ B;
iv. SOCl ₂ ；
v. R ¹ (CH ₂ ) _m R ² NH, Na ₂ CO ₃ , DCM;
vi. NaHCO ₃ , tetrakis (triphenylphosphine) palladium, propan-2-ol.

  While it is possible for a compound of the present invention to be administered as a new chemical agent, the compound of formula (I) is conveniently administered in the form of a pharmaceutical composition. Thus, in another aspect of the invention we provide a pharmaceutical composition comprising a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

  The compounds of formula (I) can be formulated for administration in any suitable manner. It can be formulated, for example, for topical administration or administration by inhalation, or more preferably for oral, transdermal or parenteral administration. The pharmaceutical composition can be in a form that allows for the sustained release of the compound of formula (I). A particularly preferred method of administration and corresponding formulation is oral administration.

  For oral administration, the pharmaceutical compositions are, for example, tablets (such as sublingual tablets) and capsules (including sustained and sustained release formulations, respectively) manufactured by conventional means using acceptable excipients, It can take the form of pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions and can be administered as those forms.

  For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerin, water and the like. Powders are made by grinding the compound to a suitable fine particle size and mixing with a similarly ground pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. Flavoring agents, preservatives, dispersing agents and coloring agents can also be present.

  Capsules can be produced by preparing a powder mixture according to the method described above and filling a shaped gelatin sheath. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can be added to increase the availability of the medicament when taking capsules.

  In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. . Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. The powder mixture can be obtained by reabsorbing a suitably pulverized compound with a diluent or base as described above and optionally a binder such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as paraffin, a quaternary salt, etc. It is prepared by mixing the compound with an accelerator and / or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucus or a solution of cellulosic or polymeric materials and applying force through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press and the result is an incompletely formed slag that collapses into granules. By adding stearic acid, stearate, talc or mineral oil, the granules can be lubricated to prevent sticking to the tableting dies. The compound of the present invention can be mixed with a free-flowing inert carrier and compressed directly into a tablet without granulation or slagging steps. Transparent or opaque protective coatings consisting of shellac sealers, sugar coatings or polymeric materials and waxy gloss coatings can be applied. Dyestuffs can be added to these coatings to distinguish different unit formulations.

  Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic medium. Suspensions can be formulated by dispersing the compound in a nontoxic medium. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

  Where appropriate, dosage unit formulations for oral administration can be microcapsules. For example, the formulation can be prepared by coating or embedding particulates with polymers, waxes, etc. to delay or sustain release.

  The compounds of the present invention can also be administered in the form of liposome administration systems such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  The compounds of the present invention can also be administered in liposome emulsion administration systems such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  The compounds of the present invention can also be administered by use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compound of the present invention can also be coupled with a soluble polymer as a pharmaceutical carrier having targeting ability. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention include, for example, polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogel cross-linked or amphiphilic block copolymers. It can be coupled to certain biodegradable polymers useful in providing sustained drug release.

  The present invention includes pharmaceutical compositions comprising 0.1 to 99.5%, more particularly 0.5 to 90% of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

  Similarly, the composition can be administered in the form of nasal, ocular, ear, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intra-articular, subcutaneous or muscle, inhaled or inhaled Also, forms well known to those skilled in the pharmaceutical industry are used.

  In the case of transdermal administration, the pharmaceutical composition can be administered in the form of a transdermal patch such as a transdermal iontophoretic patch.

  For parenteral administration, the pharmaceutical composition can be administered as an injection or as a continuous infusion (eg, intravenous, intravascular or subcutaneous). The composition can take the form of a suspension, solution or emulsion in an oil or water-based medium, and can contain pharmaceutical agents such as suspending, stabilizing and / or dispersing agents. . For administration by injection, it can take the form of a unit dose, or preferably be provided as a multi-dose with the addition of a preservative. As another form for parenteral administration, the active ingredient can be in powder form for regeneration in a suitable medium.

  The compounds of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be prepared using suitable polymers or hydrophobic materials (eg, as an acceptable emulsion in oil) or ion exchange resins, or as slightly soluble derivatives, eg, slightly soluble salts. Can be formulated as

  Alternatively, the composition can be formulated for topical administration, eg in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, gargles, impregnated dressings and sutures and aerosols. And may include suitable conventional additives such as preservatives, solvents that aid drug penetration, and emollients in ointments and creams. Such topical formulations may also contain compatible conventional carriers, such as cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers can constitute from about 1% to about 98% by weight of the formulation. More usually it constitutes up to about 80% by weight of the formulation.

  For administration by inhalation, the compounds according to the invention may conveniently comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide and other suitable gases. When used, it is administered in the form of an aerosol propellant from a pressurized pack or nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to administer a metered amount. Capsules and cartridges such as gelatin used in inhalers or ventilators can be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

  The pharmaceutical composition is usually administered in an amount effective for the treatment or prevention of the specific condition. Initial administration in humans is performed by clinical monitoring of symptoms such as symptoms in that particular condition. Usually, the composition is administered at an active agent amount of at least about 100 μg / kg. Most often it is administered in one or more doses in an amount not exceeding about 20 mg / kg / day. Preferably, in most cases, the dosage is from about 100 μg / kg / day to about 5 mg / kg / day. Particularly when administered to mammals, particularly humans, the daily dose level of the active agent is expected to be 0.1 mg / kg to 10 mg / kg, typically roughly 1 mg / kg. It will be apparent that the optimal dose will depend on standard methods for each mode of treatment and indication, taking into account the indication, its severity, route of administration, concomitant conditions, etc. In any case, the physician will determine the actual dose that is most appropriate for the individual, which will vary depending on the age, weight and response of the particular individual. The effectiveness of the actual dose selected can be readily ascertained, for example, by measuring clinical symptoms or standard anti-inflammatory indices following administration of the selected dose. The above dose is an example of an average case. There will, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. In the case of a condition or disease state to be treated according to the present invention, it may be particularly useful to maintain a consistent daily level in a subject over a long period of time, for example in a maintenance regime.

  In another aspect, the present invention provides a compound of formula (I) for use in therapy.

  Since the compounds of the present invention are inhibitors of serine / threonine kinase p38, they are also inhibitors of p38 kinase-mediated cytokine production. Included within the meaning of the term “inhibitors of serine / threonine kinase p38” are compounds that interfere with the ability of p38 to transfer a phosphate group from ATP to a protein substrate according to the assay described below.

  It will be apparent that the compounds of the invention may be selective for one or more isoforms of p38, such as p38α, p38β, p38γ and / or p38δ. In one embodiment, the compounds of the invention selectively inhibit the p38α isoform. In another embodiment, the compounds of the invention selectively inhibit the p38β isoform. In yet another embodiment, the compounds of the invention selectively inhibit the p38α and p38β isoforms. Assays to confirm the selectivity of a compound for the p38 isoform are described, for example, in WO99 / 61426, WO00 / 71535 and WO02 / 46158.

  that p38 kinase activity can be elevated (locally or throughout the body), that p38 kinase can be incorrectly activated or expressed incorrectly, p38 kinase can be expressed or activated at an inappropriate location, It is known that p38 kinase can be constitutively expressed or that p38 kinase expression can be abnormal. Similarly, cytokine production mediated by p38 kinase activity may occur at an inappropriate time, in an inappropriate location, or at an adversely high level.

  Accordingly, the present invention provides a method for treating a condition or disease state mediated by p38 kinase activity in a subject or mediated by cytokines produced by the activity of p38 kinase, wherein said subject has a therapeutically effective amount of formula (I) A method is provided comprising administering a compound. The compound may be administered in the form of single or polymorphic crystals, amorphous forms, single enantiomers, racemic mixtures, single stereoisomers, mixtures of stereoisomers, single diastereomers or mixtures of diastereomers can do.

  The present invention also includes a method of inhibiting cytokine production mediated by p38 kinase activity in a subject, eg, a human, comprising administering a therapeutic amount or a cytokine-inhibiting amount of a compound of the present invention to said subject in need of cytokine production inhibition. Provide a method. The compound may be administered in the form of single or polymorphic crystals, amorphous forms, single enantiomers, racemic mixtures, single stereoisomers, mixtures of stereoisomers, single diastereomers or mixtures of diastereomers can do. The compound may be administered in the form of single or polymorphic crystals, amorphous forms, single enantiomers, racemic mixtures, single stereoisomers, mixtures of stereoisomers, single diastereomers or mixtures of diastereomers can do.

  The present invention treats these conditions by providing a therapeutically effective amount of a compound of the present invention. “Therapeutically effective amount” means an amount that improves or reduces symptoms, an amount that reduces cytokines, an amount that inhibits cytokines, an amount that modulates kinases and / or an amount that inhibits kinases. To do. Such an amount can be readily ascertained by standard methods such as measuring cytokine levels or observing improvement in clinical symptoms. For example, a clinician can monitor an approved measurement score for anti-inflammatory treatment.

  The compounds of the invention can be administered to a subject in need of inhibition or regulation of p38 kinase, or to a subject in need of inhibition or regulation of p38 mediated cytokine production. In particular, the compound can be administered to a mammal. Such mammals can include, for example, primates such as horses, cows, sheep, pigs, mice, dogs, cats, chimpanzees, gorillas, rhesus monkeys, and most preferably humans.

  Therefore, the present invention, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic lung inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxin , Toxin toxin syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, artery Caused by aneurysm, stroke, irritable bowel syndrome, muscle degeneration, bone resorption disease, osteoporosis, diabetes, reperfusion injury, graft-versus-host reaction, allograft rejection, sepsis, systemic cachexia, infection or malignant major Cachexia, cachexia caused by acquired immune deficiency syndrome (AIDS), malaria, leprosy, infectious arthritis, leishmaniasis, Lyme disease, glomerulonephritis, gout, feeling Staining arthritis, Reiter's syndrome, traumatic arthritis, rubella arthritis, Crohn's disease, ulcerative colitis, acute synovitis, gouty arthritis, spondylitis, and non-arthritic inflammatory conditions such as hernia / destructive / Prolapsed intervertebral disc syndrome, bursitis, tendonitis, tendon synovitis, fibromyalgia syndrome and ligament contusion and local musculoskeletal contusion, other inflammatory conditions associated with pain, eg inflammation and / or trauma Treating the subject in a method of treating or alleviating symptoms in human or animal subjects suffering from cancer, such as marble bone disease, restenosis, thrombosis, angiogenesis, breast cancer, rectal cancer, lung cancer or prostate cancer There is provided a method comprising administering a top effective amount of a compound of formula (I).

  Yet another aspect of the invention includes rheumatoid arthritis, asthma, psoriasis, chronic lung inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, A method of treating a human or animal subject suffering from Parkinson's disease, epilepsy, and cancers such as breast cancer, colon cancer, lung cancer and prostate cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) I will provide a.

  Yet another aspect of the invention is rheumatoid arthritis, asthma, psoriasis, chronic lung inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and breast cancer, colon cancer, lung cancer and prostate Provided is a method of treating a human or animal subject suffering from cancer, such as cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

  Yet another aspect of the present invention provides a method for treating a human or animal subject suffering from rheumatoid arthritis, asthma, chronic lung inflammation, chronic obstructive pulmonary disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy. There is provided a method comprising administering to a subject a therapeutically effective amount of a compound of formula (I).

  Yet another aspect of the invention is chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post-operative inflammatory In a method of treating a human or animal subject suffering from any kind of pain, such as pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, retrohepatic neuralgia, inflammatory neuropathy and migraine, the subject is treated therapeutically There is provided a method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate of the compound.

  The compounds of formula (I) can be used alone or in combination with other therapeutic agents for the treatment of the above conditions. Particularly in the treatment of rheumatoid arthritis, concomitant use with other chemotherapeutic drugs or antibody drugs is conceivable. Thus, the combination therapy according to the invention comprises the step of administering at least one compound of formula (I) and at least one other pharmaceutically active agent. The compound of formula (I) and the other pharmaceutically active agent can be administered together or separately, and when administered separately, the administration can be performed individually or sequentially in any order. The amount of compound of formula (I) and other pharmaceutically active agents and the relative timing of administration are selected to achieve the desired combination therapy effect. Examples of other pharmaceutically active agents that can be used in combination with a compound of formula (I) for the treatment of rheumatoid arthritis include immunosuppressants such as amtolmetin guacil, mizoribine and rimexolone; etanercept, Anti-TNFα agents such as infliximab and diacerein; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelbekin; interferon β1 agonists; NRD-101 (Aventis), etc. Hyaluronic acid agonists; interleukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride; β-amyloid precursor protein antagonists such as reumacon; substrate metalloprotease inhibitors such as siphematat; As well as methotrexate, sul There are other disease ameliorating anti-rheumatic drugs (DMARD) such as fasalazine, cyclosporin A, hydroxychoroquine, auranofin, aurothioglucose, gold sodium thiomalate and penicillamine.

EXAMPLES The following examples are illustrative embodiments of the present invention and are not intended to limit the scope of the invention in any way. Reagents are commercially available or are prepared according to literature procedures.

  LCMS was performed on a column (3.3 cm × inner diameter 4.6 mm, 3 umABZ + PLUS) at a flow rate of 3 ml / min, an injection volume of 5 μL, room temperature and a UV detection range of 215 to 330 nm.

Intermediate 1: 6-chloro-N-cyclopropylmethylnicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 2.5 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in acetone (4 ml) and cyclopropylmethylamine (71 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N-cyclopropylmethylnicotinamide as a cream solid. NMR: δH [ ² H ₆ ] -DMSO 8.82, (2H, m), 8.23, (1H, dd), 7.63, (1H, d), 3.14, (2H, t), 1.01, (1H, m), 0.44, (2H, m), 0.22, (2H, m).

Intermediate 2: 6-Chloro-N- (4-methoxyphenyl) nicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 3 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in DCM (2 ml) and p-anisidine (123 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N- (4-methoxyphenyl) nicotinamide. _{^{NMR: δH [2 H 6]}} -DMSO 10.37, (1H, b), 8.94, (1H, d), 8.34, (1H, dd), 7.70, (1H, d), 7.66, (2H, m), 6.95, (2H, m), 3.75, (3H, s).

Intermediate 3: 6-Chloro-N- (3-methoxybenzyl) nicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 3 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in DCM (2 ml) and 3-methoxybenzylamine (137 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N- (3-methoxybenzyl) nicotinamide. NMR: δH [ ² H ₆ ] -DMSO 9.29, (1H, t), 8.88, (1H, d), 8.28, (1H, dd), 7.66, (1H, d), 7.25, (1H, t), 6.90, (2H, m), 6.83, (1H, m), 4.47, (2H, d), 3.74, (3H, s).

Intermediate 4: 6-chloro-N- (3-methylsulfonylaminobenzyl) nicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 3 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in DCM (2 ml) and 3-methylsulfonylaminobenzylamine (200 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N- (3-methylsulfonylaminobenzyl) nicotinamide. NMR: δH [ ² H ₆ ] -DMSO 9.30, (1H, t), 8.88, (1H, d), 8.28, (1H, dd), 7.67, (1H, d), 7.23, (1H, t), 7.10, (1H, s), 7.04, 91H, d), 6.97, (1H, d), 4.45, (2H, d), 2.90, (3H, s).

Intermediate 5: 6-Chloro-N- [2- (4-methylpiperazin-1-yl) phenyl] nicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 3 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in DCM (2 ml) and 1- (2-aminobenzyl) -4-methylpiperazine (205 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N- [2- (4-methylpiperazin-1-yl) phenyl] nicotinamide. Obtained. _{^{NMR: δH [2 H 6]}} -DMSO 11.62, (1H, s), 8.95, (1H, d), 8.32, (1H, dd), 8.25, (1H, d), 7.77, (1H, d), 7.34, (1H, m), 7.28, (1H, m), 7.10, (1H, m), 3.73, (2H, s), 2.56-2.20, (8H, b), 2.12, (3H, s).

Intermediate 6: 4-Methyl-N- (3-pyridin-2-yl-phenyl) -3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Benzamide
3-Iodo-4-methyl-N- (3-pyridin-2-yl-phenyl) benzamide (intermediate 7) (83 mg, 0.20 mmol), bis (pinacolato) diboron (100 mg, 0.39 mmol), potassium acetate (97 mg , 1.0 mmol) and PdCl ₂ dppf (12 mg) were heated in DMF (2.5 ml) at 80 for 4 h. The cooled reaction was absorbed onto silica, loaded onto a bond-elut (10 g, silica) and eluted with an ethyl acetate / cyclohexane gradient (0% to 100%). The solvent was removed from the product fraction under reduced pressure and the residue was triturated with ether to give 4-methyl-N- (3-pyridin-2-yl-phenyl) -3- (4,4,5 , 5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide was obtained as a white solid (31 mg). LCMS: retention time 3.69 minutes, MH ⁺ 415.

Intermediate 7: 3-Iodo-4-methyl-N- (3-pyridin-2-yl-phenyl) benzamide
3-Iodo-4-methylbenzoic acid (154 mg, 0.59 mmol) was heated in thionyl chloride (2 ml) at 80 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in acetone (3 ml) and 2- (3-aminophenyl) pyridine (100 mg, 0.59 mmol) and sodium carbonate (400 mg) were added to the solution. The reaction was stirred at room temperature for 11 days, filtered, and the filtrate was reduced in vacuo to dryness. The residue was dissolved in ether, filtered through Bond-Elut (1 g, silica) and washed with ether. The solvent was removed from the combined filtrate and washings to give 3-iodo-4-methyl-N- (3-pyridin-2-yl-phenyl) benzamide as a cream foam. NMR: δHCDCl ₃ 8.70, (1H, dt), 8.33, (1H, d), 8.18, (1H, t), 7.93-7.89, (2H, m), 7.79-7.75, (4H, m), 7.50, (1H, t), 7.35, (1H, d), 7.26, (1H, m), 2.51, (3H, s).

Intermediate 8: N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide
N-cyclopropyl-3-iodo-4-methylbenzamide (Intermediate 9) (1.1 g, 3.64 mmol), bis (pinacolato) diboron (1.85 g, 7.28 mmol), potassium acetate (1.79 g, 18.2 mmol) and PdCl ₂ dppf (55 mg) was heated in DMF (30 ml) at 85 ° C. for 4.5 hours. The cooled reaction was absorbed onto silica, loaded onto a Bond-Elut (10 g, silica) and eluted with an ethyl acetate / cyclohexane gradient (0% to 100%). The solvent is distilled off from the product fraction under reduced pressure and the residue is triturated with cyclohexane to give N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1, 3,2] Dioxaborolan-2-yl) -benzamide was obtained as a white solid (650 mg). NMR: δH [ ² H ₆ ] -DMSO 8.40, (1H, d), 8.06, (1H, d), 7.76, (1H, dd), 7.23, (1H, d), 2.82, (1H, m), 2.48, (3H, s), 1.30, (12H, s), 0.66, (2H, m), 0.56, (2H, m).

Intermediate 9: N-cyclopropyl-3-iodo-4-methylbenzamide
3-Iodo-4-methylbenzoic acid (1.0 g, 3.8 mmol) was heated in thionyl chloride (10 ml) at 80 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in DCM (10 ml) and cyclopropylamine (0.32 ml) and sodium carbonate (2.0 g) were added to the solution. The reaction was stirred at room temperature for 18 hours, filtered, and the filtrate was reduced in vacuo to dryness. The residue was triturated with ether to give N-cyclopropyl-3-iodo-4-methylbenzamide as a white solid (1.1 g). _{^{NMR: δH [2 H 6]}} -DMSO 8.46, (1H, d), 8.24, (1H, d), 7.74, (1H, dd), 7.38, (1H, d), 2.82, (1H, m), 2.38, (3H, s), 0.67, (2H, m), 0.55, (2H, m).

Intermediate 10: N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide
4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid (Intermediate 17) (2.0 g, 7.63 mmol), DIPEA (4 ml , 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 minutes. Cyclopropylmethylamine (568 mg, 8.01 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the reaction was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), dried (magnesium sulfate) and the solvent was removed under reduced pressure. The residue was absorbed on silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4: 1). The solvent was distilled off from the product fraction under reduced pressure to give N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2- Yl) -benzamide was obtained (1.73 g). LCMS: retention time 3.47 min, MH ⁺ 316. _{^{NMR: δH [2 H 6]}} -DMSO 8.54, (1H, t), 8.11, (1H, d), 7.82, (1H, dd), 7.26, (1H, d), 3.12, (2H, t), 1.32, (12H, s), 1.03, (1H, m), 0.42, (2H, m), 0.22, (2H, m).

Intermediate 11: 4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) -benzamide
4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) was dissolved in DMF (20 ml) and stirred at room temperature for 15 minutes. 2-Aminothiazole (801 mg, 8.01 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the reaction was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), dried (magnesium sulfate) and the solvent was removed under reduced pressure. The residue was absorbed on silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4: 1). The solvent was removed from the product fraction under reduced pressure to give 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- ( Thiazol-2-yl) -benzamide was obtained (1.72 g). LCMS: retention time 3.66 min, MH ⁺ 345. NMR: δH [ ² H ₆ ] -DMSO 12.65, (1H, b), 8.32, (1H, d), 8.08, (1H, dd), 7.56, (1H, d), 7.35, (1h, d), 7.28, (1H, d), 2.54, (3H, s), 1.34, (12H, s).

Intermediate 12: 4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl) -benzamide
4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) was dissolved in DMF (20 ml) and stirred at room temperature for 15 minutes. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the reaction was partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous phase was extracted with ethyl acetate (2 x 250ml). The combined organic extracts were dehydrated (magnesium sulfate) and the solvent was removed under reduced pressure. The residue was absorbed on silica and purified by flash column chromatography eluting with cyclohexane / ethyl acetate (4: 1 and then 1: 1). The solvent was removed from the product fraction under reduced pressure to give 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- ( Thiadiazol-2-yl) -benzamide was obtained (0.95 g). LCMS: retention time 3.34 min, MH ⁺ 346. _{^{NMR: δH [2 H 6]}} -DMSO 13.08, (1H, b), 9.22, (1H, s), 8.35, (1H, d), 8.11, (1H, dd), 7.38, (1H, d), 2.55, (3H, s), 1.34, (12H, s).

Intermediate 13: N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3-furamide
N- (3-iodo-4-methylphenyl) -3-furamide (intermediate 15) (2.5 g, 7.64 mmol), bis (pinacolato) diboron (2.13 g, 8.41 mmol), potassium acetate (825 mg, 8.41 mmol) And a solution of PdCl ₂ dppf (312 mg, 0.38 mmol) in DMF (20 ml) was heated at 80 ° C. for 20 hours. The cooled reaction was absorbed onto silica, loaded onto a Bond-Elut (silica, 10 g) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under reduced pressure, dissolved in DMF (40 ml), bis (pinacolato) diboron (7.76 g, 30.57 mmol), potassium acetate (3.0 g, 30.57 mmol) and PdCl ₂ dppf (249 mg, 0.306 mmol) And reacted at 80 ° C. for 23 hours. The cooled reaction was absorbed onto silica, loaded onto a bond-elut (silica, 2 × 10 g) and eluted with a cyclohexane / ethyl acetate gradient. The product fractions were concentrated under reduced pressure to give N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl]- 3-Framide was obtained. LCMS: retention time 3.55 min, MH ⁺ 328. _{^{NMR: δH [2 H 6]}} -DMSO 9.86, (1H, b), 8.36, (1H, m), 7.86-7.82, (2H, m), 7.77, (1H, t), 7.14, (1H, d ), 6.99, (1H, m), 2.41, (3H, s), 1.30, (12H, s).

Intermediate 14: N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene-3-amide
N- (3-iodo-4-methylphenyl) thiophene-3-amide (intermediate 16) (2.64 g, 7.64 mmol), bis (pinacolato) diboron (2.13 g, 8.41 mmol), potassium acetate (825 mg, 8.41 mmol) ) And PdCl ₂ dppf (312 mg, 0.38 mmol) in DMF (20 ml) was heated at 80 ° C. for 20 hours. The cooled reaction was absorbed onto silica, loaded onto a Bond-Elut (silica, 10 g) and eluted with a cyclohexane / ethyl acetate gradient. The product fraction was concentrated under reduced pressure, dissolved in DMF (20 ml), and bis (pinacolato) diboron (1.77 g, 7.0 mmol), potassium acetate (687 mg, 7.0 mmol) and PdCl ₂ dppf (143 mg, 0.175 mmol). The reaction was allowed to proceed at 80 ° C. for 16 hours. The cooled reaction was absorbed onto silica, loaded onto a Bond-Elut (silica, 10 g) and eluted with a cyclohexane / ethyl acetate gradient. The product fraction was concentrated under reduced pressure to give N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene -3-amide was obtained. LCMS: retention time 3.65 min, MH ⁺ 344. _{^{NMR: δH [2 H 6]}} -DMSO 9.99, (1H, b), 8.35, (1H, s), 7.90, (1H, d), 7.85, (1H, dd), 7.63, (2H, m), 7.14, (1H, d), 2.42, (3H, s), 1.30, (12H, s).

Intermediate 15: N- (3-iodo-4-methylphenyl) -3-furamide
A solution of 3-furonic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) was stirred at room temperature for 15 minutes. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases were washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dehydrated (magnesium sulfate) and absorbed onto silica. The silica was loaded onto a flash silica column and eluted with cyclohexane / ethyl acetate (3: 1). The solvent was removed from the product fraction under reduced pressure to give N- (3-iodo-4-methylphenyl) -3-furamide. LCMS: retention time 3.52 min, MH ⁺ 328. NMR: δH [ ² H ₆ ] -DMSO 9.92, (1H, b), 8.36, (1H, d), 8.23, (1H, d), 7.80, (1H, t), 7.66, (1H, dd), 7.29, (1H, d), 6.98, (1H, d), 2.33, (3H, s).

Intermediate 16: A solution of N- (3-iodo-4-methylphenyl) thiophene-3- amidothiophene-3-carboxylic acid (2.75 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml). Stir at room temperature for 15 minutes. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases were washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dehydrated (magnesium sulfate) and absorbed onto silica. The silica was loaded onto a flash silica column and eluted with cyclohexane / ethyl acetate (4: 1). The solvent was removed from the product fraction under reduced pressure to give N- (3-iodo-4-methylphenyl) thiophene-3-amide. LCMS: retention time 3.69 min, MH ⁺ 344. NMR: δH [ ² H ₆ ] -DMSO 10.06, (1H, b), 8.34, (1H, m), 8.29, (1H, d), 7.70, (1H, dd), 7.66, (1H, dd), 7.62, (1H, dd), 7.30, (1H, d), 2.34, (3H, s).

Intermediate 17: 4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid
Of 3-iodo-4-methylbenzoic acid (10 g, 38.16 mmol), bis (pinacolato) diboron (14.5 g, 57.24 mmol), potassium acetate (18.73 g, 190.8 mmol) and PdCl ₂ dppf (3.12 g, 3.8 mmol) DMF (200 ml) solution was heated at 80 ° C. for 21 hours. The solvent was distilled off from the cooled reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate (300 ml) and hydrochloric acid (2N, 300 ml) and filtered through celite. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 300 ml). The combined organic extracts were washed with brine (500 ml) and dehydrated (magnesium sulfate). The solvent was removed under reduced pressure and the residue was absorbed onto silica and loaded onto a silica flash column. It was eluted with cyclohexane / ethyl acetate (5: 1). The product fraction was concentrated under reduced pressure to give 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid. LCMS: Retention time 3.65 minutes. NMR: δH [ ² H ₆ ] -DMSO 12.83, (1H, b), 8.23, (1H, d), 7.89, (1H, dd), 7.29, (1H, d), 2.51, (3H, s), 1.30, (12H, s).

Intermediate 18: N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-pyrrolidin-1-yl- Isonicotinamide bis (pinacolato) diborane (7.24 g, 28.5 mmol) was added to N- (3-iodo-4-methylphenyl) -2-pyrrolidin-1-yl-isonicotinamide (intermediate 19) (7.73 g, 19 mmol) in dimethylformamide (100 ml), potassium acetate (9.32 g, 95 mmol) and PdCl ₂ dppf were added and the reaction was heated at 80 ° C. for 16 hours under nitrogen atmosphere. The reaction was cooled and the solvent removed under reduced pressure. The residue was taken up in chloroform (150 ml), washed with water (3 × 100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography (20:80 ethyl acetate: cyclohexane to 50:50 ethyl acetate: cyclohexane). N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -2-pyrrolidin-1-yl-isonicotinamide Obtained as a white solid (1.5 g, 3.7 mmol). LCMS: retention time 2.90 min, MH ⁺ 408. NMR: δH-CDCl ₃ 8.27 (1H, d), 7.99 (1H, dd), 7.76 (1H, b), 7.65 (1H, d), 6.20 (1H, d), 6.82 (1H, b), 6.77 ( 1H, b), 3.52 (4H, apparently t), 2.52 (3H, s), 2.25 (4H, m).

Intermediate 19: N- (3-iodo-4-methylphenyl) -2-pyrrolidin-1-yl-isonicotinamide
A solution of N- (3-iodo-4-methylphenyl) -2-chloro-isonicotinamide (Intermediate 20) (7.00 g, 18.8 mmol) in pyrrolidine (20 ml) was heated at 80 ° C. for 16 hours under a nitrogen atmosphere. did. Excess pyrrolidine was removed under reduced pressure and the residue was triturated with diethyl ether (20 ml). The resulting solid was collected by filtration and dried in vacuo to give N- (3-iodo-4-methylphenyl) -2-pyrrolidin-1-yl-isonicotinamide as a pale yellow solid (7.73 g, 18 mmol). LCMS: retention time 2.77 minutes, MH ⁺ 408. NMR: δH [ ² H ₆ ] -DMSO 10.29 (1H, s), 8.29 (1H, d), 8.20 (1H, d), 7.71 (1H, dd), 7.72 (1H, dd), 6.97 (1H, brd ), 6.88 (1H, b), 3.45 (2H, apparently t), 3.09 (2H, m), 2.35 (3H, s), 1.98 (2H, m), 1.82 (2H, m).

Intermediate 20: 2-Chloro-N- (3-iodo-4-methylphenyl) -isonicotinamide
Dichloroformamide (50 ml) of 2-chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethylamine (10.9 ml, 63 mmol) and 4-iodo-3-methylaniline (5.00 g, 21 mmol) The solution was heated under nitrogen for 16 hours. The reaction was cooled and removed under reduced pressure, and the residue was taken up in methylene chloride (150 ml). The organic solution was washed with water (3 x 100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography (40:60 ethyl acetate: cyclohexane) to give 2-chloro-N- (3-iodo-4-methylphenyl) -isonicotinamide as a white solid (7.00 g, 18.8 mmol). LCMS: retention time 3.59 min, MH ⁺ 373. NMR: δH [ ² H ₆ ] -DMSO 10.52 (1H, s), 8.62 (1H, d), 8.29 (1H, d), 7.99 (1H, b), 7.87 (1H, dd), 7.70 (1H, dd ), 7.34 (1H, d), 2.36 (3H, s).

Intermediate 21: 6-Chloro-N-cyclopropylmethylnicotinamide
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated to reflux in thionyl chloride (2 ml) for 2.5 hours. The reaction solution was allowed to cool to room temperature, and excess thionyl chloride was distilled off under reduced pressure. The residue was dissolved in acetone (4 ml) and cyclopropylmethylamine (71 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hours, filtered, and the filtrate was reduced in vacuo to dryness to give 6-chloro-N-cyclopropylmethylnicotinamide as a cream solid. NMR: δH [ ² H ₆ ] -DMSO 8.82, (2H, m), 8.23, (1H, dd), 7.63, (1H, d), 3.14, (2H, t), 1.01, (1H, m), 0.44, (2H, m), 0.22, (2H, m).

General Law A
6-Bromonicotinic acid (100 mg, 0.5 mmol) was heated in thionyl chloride (0.63 ml) at 95 ° C. for 2 hours. Excess thionyl chloride was distilled off under reduced pressure and the residue was dissolved in DCM (2 ml). To this solution was added amine (0.5 mmol) and sodium carbonate (100 mg) and the reaction was stirred at room temperature for 2 hours. The reaction was filtered and the residue was washed with DCM. The combined filtrate and washings were reduced to dryness to give the desired 6-chloronicotinamide.

Intermediate 32: 6-Chloro-N-cyclobutylmethylnicotinamide Using general method A, 6-chloro-N-cyclobutylmethylnicotinamide was prepared from cyclobutylmethylamine.

_{^{NMR: δH [2 H 6]}} -DMSO 8.81, (1H, d), 8.70, (1H, bt), 8.22, (1H, dd), 7.64, (1H, d), 3.30, (2H, t), 2.52, (1H, m), 1.99, (2H, m), 1.81, (2H, m), 1.73, (2H, m).

Intermediate 33: 6-chloro-N- (1-methylpropyl) nicotinamide Using general method A, 6-chloro-N- (1-methylpropyl) nicotinamide was prepared from 1-methylpropylamine.

NMR: δH [ ² H ₆ ] -DMSO 8.82, (1H, d), 8.42, (1H, d), 8.24, (1H, dd), 7.64, (1H, d), 3.91, (1H, m), 1.51, (2H, m), 1.15, (3H, d), 0.87, (3H, t).

Intermediate 34: N-cyclopropyl-5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide
3-bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (intermediate 35, 900 mg), bispinacolatodiboron (4.5 g), potassium acetate (2.1 g) and PdCl ₂ dppf (75 mg) in DMF (40 ml) and heated at 100 ° C. for 18 hours. The cooled reaction liquid was absorbed in silica and placed on SPE (Si 2 × 10 g). SPE was eluted with an ethyl acetate / cyclohexane gradient (0% to 6.25% ethyl acetate). The solvent is distilled off from the product fraction under reduced pressure and the residue is recrystallized from cyclohexane to give N-cyclopropyl-5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl -[1,3,2] Dioxaborolan-2-yl) -benzamide (260 mg) was obtained.

LCMS: MH ⁺ 320, retention time 3.39 minutes.

Intermediate 35: 3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide
3-Fluoro-4-methylbenzoic acid (462 mg, 3.0 mmol) was added to a stirred mixture of bromine (2.31 ml, 45 mmol) and iron powder (252 mg, 4.5 mmol) under nitrogen. The reaction was stirred at 20 ° C. for 4 hours and left for 16 hours. Sodium thiosulfate solution (200 ml) was added and the product was extracted with ethyl acetate (3 x 150 ml). The ethyl acetate extracts were combined and the solvent was distilled off under reduced pressure. The crude product (mixture of isomers) was dissolved in dimethylformamide (7 ml). Cyclopropylamine (208 μL, 3.0 mmol), HOBT (405 mg, 3.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (575 mg, 3.0 mmol) and DIPEA (525 μL, 3.0 mmol) Added to the stirred solution. The reaction was stirred at 20 ° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The combined ethyl acetate extracts were washed with sodium bicarbonate aqueous solution and hydrochloric acid (0.5M) in this order and dehydrated (magnesium sulfate). Ethyl acetate was distilled off under reduced pressure and the residue was purified by silica biotage chromatography eluting with cyclohexane: ethyl acetate (6: 1) to give 3-bromo-N-cyclopropyl-5-fluoro-4. -Methylbenzamide was obtained (359 mg, 44%).

NMR: δH-CDCl ₃ 7.68, (1H, s), 7.39, (1H, d), 6.19, (1H, bs), 2.88, (1H, m), 2.36, (3H, d), 0.88, (2H , M), 0.63, (2H, m). LCMS: MH ⁺ 272.

Intermediate 36: {5-[(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid
A solution of N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5 g) in THF (75 ml) was cooled to 0 ° C. and sodium hydride (60%, 1.23 g) was added to 10 ° C. Added in small portions over a period of minutes. When effervescence ceased, the reaction was cooled to −75 ° C. and n-butyllithium (1.6M hexane solution, 20 ml) was added over 25 minutes while maintaining the temperature below −70 ° C. Triisopropyl borate (8 ml) was added to the reaction over 10 minutes and the reaction was stirred at -70 ° C. for 4 hours. The reaction was quenched with water (20 ml) and the mixture was warmed to 5 ° C. The reaction was concentrated under reduced pressure and the residue was partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulfate) and reduced in vacuo to dryness. The residue was dissolved in DCM / ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate / DCM gradient (5% to 100% ethyl acetate) followed by methanol. The product fractions were combined and the solvent was removed under reduced pressure to give {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid. LCMS: MH ⁺ 238, retention time 2.19 minutes.

Intermediate 37: N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide
N-iodosuccinimide (22.5 g) was added in portions to a solution of 3-fluoro-4-methylbenzoic acid (15.4 g) in trifluoromethanesulfonic acid (100 ml) at 0 ° C. over 3 hours, and the reaction solution was then added. The temperature was raised overnight to room temperature. The reaction mixture was poured into ice / water (400 ml) and the precipitate was filtered and washed with water. The remaining solid was dissolved in ethyl acetate, washed with aqueous sodium thiosulfate solution (twice), then with brine, dried (magnesium sulfate), and the solvent was removed under reduced pressure. The residue was mixed with thionyl chloride (30 ml) and heated at 100 ° C. for 2.5 hours. Excess thionyl chloride was removed from the cooled reaction under reduced pressure and the residue was dissolved in DCM (100 ml). Sodium carbonate (25 g) and cyclopropylamine (13 ml) were added to the solution and the reaction was stirred at room temperature for 72 hours. The reaction was filtered and washed with residual DCM and ethyl acetate. The solvent was distilled off from the combined filtrate and washings under reduced pressure. The residue was absorbed onto silica and chromatographed on a flash silica column eluting with an ethyl acetate / cyclohexane gradient (22% to 28% ethyl acetate). Appropriate fractions were reduced in vacuo to dryness to give N-cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide.

  LCMS; MH + 320, retention time 3.16 minutes.

Intermediate 38: 6- {5-[(Cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinic acid
N-cyclopropyl-5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (3.2 g), 6-chloro Methyl nicotinate (1.73 g), tetrakis (triphenylphosphine) palladium (210 mg) and aqueous sodium bicarbonate solution (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90 ° C. for 18 hours. The reaction was allowed to cool and propan-2-ol was removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (twice). The organic extract was washed with brine, dried (magnesium sulfate), reduced in vacuo and dried. The resulting foam was triturated with ether to give 6- {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} nicotinic acid as a solid.

  LCMS: MH + 315, retention time 2.87 minutes.

Intermediate 39: (2-Ethylcyclopropyl) methylamine
A THF solution of 2-ethylcyclopropylcarboxamide (250 mg, 2.2 mmol) was heated to reflux. Borane-dimethyl sulfide (1M DCM solution, 3.2 ml, 3.2 mmol) was added dropwise over 30 minutes and the reaction was refluxed for 16 hours. Hydrochloric acid (6N, 0.5 ml) was added dropwise and the mixture was heated to reflux for 30 minutes. The cooled reaction mixture was diluted with water (20 ml), washed with ether (50 ml) and basified with sodium hydroxide (6N). The aqueous phase was extracted with ether (3 x 50 ml) and ethyl acetate (50 ml). The combined organic extracts were dehydrated (magnesium sulfate), acidified with hydrogen chloride (3.3M methanol solution), reduced in vacuo and evaporated to dryness to give (2-ethylcyclopropyl) methylamine (230mg). It was.

NMR: δH [ ² H ₆ ] -DMSO 7.85, (3H, b), 2.66, (2H, d), 1.30-1.13, (2H, m), 0.91, (3H, t), 0.77-0.66, (2H M), 0.46, (1H, m), 0.33, (1H, m).

General Law B
A solution of 2-chloropyridine (0.05 mmol), phenylpinacol borane (0.05 mmol), tetrakis (triphenylphosphine) palladium (1 mg) and aqueous sodium carbonate (0.25 ml) in propan-2-ol (1 ml) at 85 ° C. Heated under nitrogen for 18 hours. The cooled reaction was diluted with ethyl acetate (4 ml) and methanol (2 ml) and filtered through SCX Bond-Elut (1 g). The product was eluted with a methanol solution of 10% ammonia (specific gravity 0.88). The solvent was removed and the residue was triturated with ether.

N- (3- [5- (cyclopropylmethyl-carbamoyl) -pyridin-2-yl] -4-methyl-phenyl) -2-pyrrolidin-1-yl-isonicotinamide

6-chloro-N-cyclopropylmethylnicotinamide (intermediate 1) (25 mg, 0.098 mmol) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2 ] Dioxaborolan-2-yl) -phenyl] -2-pyrrolidin-1-yl-isonicotinamide (Intermediate 18) (30 mg, 0.074 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis (triphenylphosphine) Palladium (4 mg) was heated at 80 ° C. in DMF (1 ml) for 18 hours. The reaction was absorbed onto silica, loaded onto Bond-Elut (10 g, silica) and eluted with ethyl acetate / cyclohexane (0% to 100%), then acetone and methanol. The solvent was removed from the product fraction under reduced pressure and the residue was triturated with ether to give N- (3- [5- (cyclopropylmethyl-carbamoyl) -pyridin-2-yl] -4-methyl. -Phenyl) -2-pyrrolidin-1-yl-isonicotinamide was obtained as a white solid (20 mg). LCMS: retention time 2.42 min, MH ⁺ 456. NMR: δH [ ² H ₆ ] -DMSO 10.32, (1H, s), 9.09, (1H, s), 8.82, (1H, t), 8.28, (1H, m), 8.19, (1H, m), 7.85, (1H, t), 7.76, (1H, m), 7.64, (1H, m), 7.31, (1H, m), 6.98, (1H, m), 6.88, (1H, s), 3.43, (4H, m), 3.18, (2H, m), 2.31, (3H, s), 1.95, (4H, m), 1.07, (1H, m), 0.45, (2H, m), 0.25, (2H , M).

N-cyclopropylmethyl-6- [2-methyl-5- (3-pyridin-2-yl-phenylcarbamoyl) -phenyl] -nicotinamide

6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5 mg, 0.073 mmol) and 4-methyl-N- (3-pyridin-2-yl-phenyl) -3- (4,4,5 , 5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (intermediate 6) (30 mg, 0.072 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis (triphenylphosphine) palladium (4 mg) was heated at 90 ° C. in DMF (1 ml) for 4 hours. The reaction was absorbed on silica, loaded onto a bond-elut (5 g, silica), eluted with ethyl acetate / cyclohexane (0% to 100%) and then acetone. The solvent is distilled off from the product fraction under reduced pressure and the residue is triturated with ether to give N-cyclopropylmethyl-6- [2-methyl-5- (3-pyridin-2-yl-phenylcarbamoyl). ) -Phenyl] -nicotinamide was obtained as a white solid (20 mg). LCMS: 3.18 min retention time, MH ⁺ 463. NMR: δH [ ² H ₆ ] -DMSO 10.43, (1H, s), 9.14, (1H, s), 8.86, (1H, t), 8.69, (1H, s), 8.53, (1H, s), 8.34, (1H, d), 8.11, (1H, s), 8.01, (1H, d), 7.95-7.89, (3H, m), 7.81-7.78, (2H, m), 7.53-7.46, (2H , M), 7.38, (1H, t), 3.21, (2H, t), 2.44, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m ).

6- (5-Cyclopropylcarbamoyl-2-methyl-phenyl) -N-cyclopropylmethyl-nicotinamide

6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (25.5 mg, 0.10 mmol) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1, 3,2] Dioxaborolan-2-yl) -benzamide (Intermediate 8) (30 mg, 0.10 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis (triphenylphosphine) palladium (4 mg) at 90 ° C. in DMF ( In 1 ml) for 3 hours. The reaction was absorbed on silica, loaded onto a bond-elut (5 g, silica), eluted with ethyl acetate / cyclohexane (0% to 100%) and then acetone. The solvent is removed from the product fraction under reduced pressure, the residue is triturated with ether, and 6- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -N-cyclopropylmethyl-nicotinamide is creamed. Obtained as a colored solid. LCMS: retention time 2.70 min, MH ⁺ 350. NMR: δH [ ² H ₆ ] -DMSO 9.11, (1H, s), 8.84, (1H, t), 8.48, (1H, d), 8.31, (1H, dd), 7.88, (1H, s), 7.81, (1H, d), 7.70, (1H, d), 7.41, (1H, d), 3.20, (1H, t), 2.86, (1H, m), 2.37, (3H, s), 1.06, (1H, m), 0.69, (2H, m), 0.57, (2H, m), 0.46, (2H, m), 0.26, (2H, m).

N-cyclopropylmethyl-6- [5- (thiadiazol-2-ylcarbamoyl) -2-methyl-phenyl] -nicotinamide

Using general method B, N-cyclopropylmethyl-6- [5- (thiadiazol-2-ylcarbamoyl) -2-methyl-phenyl] -nicotinamide is converted to 6-chloro-N-cyclopropylmethylnicotinamide (intermediate). 1) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl) -benzamide (intermediate) 12) Manufactured from. LCMS: retention time 2.79 min, MH ⁺ 394. NMR: δH [ ² H ₆ ] -DMSO 13.14, (1H, b), 9.24, (1H, s), 9.14, (1H, s), 8.86, (1H, t), 8.35, (1H, d), 8.25, (1H, s), 8.10, (1H, d), 7.82, (1H, d), 7.54, (1H, d), 3.21, (2H, t), 2.46, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m).

N-cyclopropylmethyl-6- [5- (thiazol-2-ylcarbamoyl) -2-methyl-phenyl] -nicotinamide

Using general method B, N-cyclopropylmethyl-6- [5- (thiazol-2-ylcarbamoyl) -2-methyl-phenyl] -nicotinamide is converted to 6-chloro-N-cyclopropylmethylnicotinamide (intermediate). 1) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) -benzamide (intermediate) 11) Manufactured from. LCMS: retention time 2.99 minutes, MH ⁺ 393. NMR: δH [ ² H ₆ ] -DMSO 12.71, (1H, b), 9.13, (1H, s), 8.86, (1H, t), 8.34, (1H, d), 8.21, (1H, s), 8.07, (1H, d), 7.81, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.29, (1H, d), 3.21, (2H, t), 2.45, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m).

6- [5- (Cyclopropylmethylcarbamoyl) -2-methyl-phenyl] -N-cyclopropylmethyl-nicotinamide

Using general method B, 6- [5- (cyclopropylmethyl) carbamoyl-2-methyl-phenyl] -N-cyclopropylmethyl-nicotinamide was converted to 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1 ) And N- (cyclopropylmethyl) -4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (intermediate 10) did. LCMS: retention time 2.87 min, MH ⁺ 364. _{^{NMR: δH [2 H 6]}} -DMSO 9.10, (1H, s), 8.83, (1H, t), 8.60, (1H, t), 8.30, (1H, dd), 7.92, (1H, s), 7.84, (1H, d), 7.71, (1H, d), 7.41, (1H, d), 3.19, (2H, t), 3.13, (2H, t), 2.37, (3H, s), 1.03, (2H, m), 0.44, (4H, m), 0.23, (4H, m).

N-cyclopropylmethyl-6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide

Using General Method B, N-cyclopropylmethyl-6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide is converted to 6-chloro-N-cyclopropylmethylnicotinamide ( Intermediate 1) and N- [4-Methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3-furamide (Intermediate 13) ). LCMS: retention time 2.96 minutes, MH ⁺ 376. _{^{NMR: δH [2 H 6]}} -DMSO 9.99, (1H, s), 9.10, (1H, s), 8.83, (1H, t), 8.38, (1H, s), 8.30, (1H, d), 7.80, (2H, s), 7.75, (1H, d), 7.66, (1H, d), 7.30, (1H, d), 3.20, (2H, t), 2.31, (3H, s), 1.06, (1H, m), 0.46, (2H, m), 0.27, (2H, m).

N-cyclopropylmethyl-6- [2-methyl-5- (thiophen-3-ylcarbonylamino) -phenyl] -nicotinamide

Using general method B, N-cyclopropylmethyl-6- [2-methyl-5- (thiophen-3-ylcarbonylamino) -phenyl] -nicotinamide is converted to 6-chloro-N-cyclopropylmethylnicotinamide ( Intermediate 1) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene-3-amide (intermediate 14) Manufactured from. LCMS: retention time 3.07 minutes, MH ⁺ 392. _{^{NMR: δH [2 H 6]}} -DMSO 10.11, (1H, s), 9.11, (1H, s), 8.83, (1H, t), 8.35, (1H, s), 8.30, (1H, dd), 7.85, (1H, s), 7.78, (1H, d), 7.67-7.63, (3H, m), 7.31, (1H, d), 3.20, (2H, t), 2.31, (3H, s), 1.06, (1H, m), 0.46, (1H, m), 0.27, (1H, m).

6- (5-Cyclopropylcarbamoyl-2-methyl-phenyl) -N- (4-methoxyphenyl) -nicotinamide

Using general method B, 6- [5-cyclopropylcarbamoyl-2-methyl-phenyl] -N- (4-methoxyphenyl) -nicotinamide is converted to 6-chloro-N- (4-methoxyphenyl) nicotinamide ( Prepared from Intermediate 2) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate 8) did. LCMS: retention time 2.96 min, MH ⁺ 402. _{^{NMR: δH [2 H 6]}} -DMSO 10.38, (1H, s), 9.20, (1H, s), 8.49, (1H, d), 8.40, (1H, dd), 7.91, (1H, s), 7.82, (1H, d), 7.76, (1H, d), 7.71, (2H, d), 7.43, (1H, d), 6.96, (2H, d), 3.76, (3H, s), 2.87, (1H, m), 2.40, (3H, s), 0.70, (2H, m), 0.58, (2H, m).

N- (4-Methoxyphenyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- (4-methoxyphenyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide is converted to 6-chloro-N- (4-methoxy Phenyl) nicotinamide (Intermediate 2) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl ) -Benzamide (Intermediate 12). LCMS: retention time 3.05 minutes, MH ⁺ 446. _{^{NMR: δH [2 H 6]}} -DMSO 13.15, (1H, b), 10.41, (1H, s), 9.24, (2H, m), 8.45, (1H, dd), 8.28, (1H, s), 8.11, (1H, d), 7.88, (1H, d), 7.71, (2H, d), 7.56, (1H, d), 6.97, (2H, d), 3.76, (3H, s), 2.48, (3H, s).

N- (4-Methoxyphenyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- (4-methoxyphenyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide was converted to 6-chloro-N- (4-methoxy Phenyl) nicotinamide (Intermediate 2) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) ) -Benzamide (Intermediate 11). LCMS: retention time 3.22 min, MH ⁺ 445. _{^{NMR: δH [2 H 6]}} -DMSO 12.72, (1H, s), 10.40, (1H, s), 9.22, (1H, d), 8.44, (1H, dd), 8.24, (1H, s), 8.09, (1H, d), 7.87, (1H, d), 7.71, (2H, d), 7.58, (1H, d), 7.53, (1H, d), 7.30, (1H, d), 6.97, (2H, d), 3.76, (3H, s), 2.48, (3H, s).

6- (5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- (4-methoxyphenyl) -nicotinamide

Using general method B, 6- [5-cyclopropylmethylcarbamoyl-2-methyl-phenyl] -N- (4-methoxyphenyl) -nicotinamide is converted to 6-chloro-N- (4-methoxyphenyl) nicotinamide. (Intermediate 2) and N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate 10) Manufactured from. LCMS: retention time 3.12 min, MH ⁺ 416. NMR: δH [ ² H ₆ ] -DMSO 10.39, (1H, s), 9.21, (1H, d), 8.63, (1H, t), 8.41, (1H, dd), 7.96, (1H, s), 7.86, (1H, d), 7.79, (1H, d), 7.71, (2H, d), 7.44, (1H, d), 6.96, (2H, d), 3.76, (3H, s), 3.15, (2H, t), 2.41, (3H, s), 1.03, (1H, m), 0.43, (2H, m), 0.23, (2H, m).

6- [5- (Fura-3-ylcarbonylamino) -2-methyl-phenyl] -N- (4-methoxyphenyl) -nicotinamide

Using general method B, 6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -N- (4-methoxyphenyl) -nicotinamide is converted to 6-chloro-N- (4- Methoxyphenyl) nicotinamide (intermediate 2) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3 Prepared from furamide (intermediate 13). LCMS: retention time 3.19 min, MH ⁺ 428. NMR: δH [ ² H ₆ ] -DMSO 10.38, (1H, s), 10.00, (1H, s), 9.19, (1H, s), 8.38, (2H, m), 7.83, (1H, s), 7.80, (1H, s), 7.76, (1H, s), 7.73-7.69, (3H, m), 7.32, (1H, s), 7.01, (1H, s), 6.96, (2H, d), 3.76, (3H, s), 2.34, (3H, s).

6- (5-Cyclopropylcarbamoyl-2-methyl-phenyl) -N- (3-methoxybenzyl) -nicotinamide

Using general method B, 6- [5-cyclopropylcarbamoyl-2-methyl-phenyl] -N- (3-methoxybenzyl) -nicotinamide is converted to 6-chloro-N- (3-methoxybenzyl) nicotinamide ( Prepared from intermediate 3) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (intermediate 8) did. LCMS: retention time 2.94 minutes, MH ⁺ 416. NMR: δH [ ² H ₆ ] -DMSO 9.29, (1H, t), 9.15, (1H, s), 8.48, (1H, d), 8.35, (1H, d), 7.89, (1H, s), 7.81, (1H, d), 7.72, (1H, d), 7.41, (1H, d), 7.26, (1H, t), 6.93, (2H, m), 6.84, (1H, s), 4.51, (2H, d), 3.75, (3H, s), 2.86, (1H, m), 2.38, (3H, s), 0.69, (2H, m), 0.57, (2H, m).

N- (3-Methoxybenzyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- (3-methoxybenzyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide was converted to 6-chloro-N- (3-methoxy Benzyl) nicotinamide (Intermediate 3) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl) ) -Benzamide (Intermediate 12). LCMS: Retention time 3.02 minutes, MH ⁺ 460. _{^{NMR: δH [2 H 6]}} -DMSO 13.14, (1H, b), 9.32, (1H, t), 9.24, (1H, s), 9.18, (1H, d), 8.40, (1H, dd), 8.26, (1H, s), 8.10, (1H, d), 7.84, (1H, d), 7.55, (1H, d), 7.27, (1H, t), 6.94, (2H, m), 6.84, (1H, d), 4.53, (2H, d), 3.75, (3H, s), 2.46, (3H, s).

N- (3-methoxybenzyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using General Method B, N- (3-methoxybenzyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide was converted to 6-chloro-N- (3-methoxy Benzyl) nicotinamide (Intermediate 3) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazol-2-yl) ) -Benzamide (Intermediate 11). LCMS: retention time 3.20 min, MH ⁺ 459. _{^{NMR: δH [2 H 6]}} -DMSO 12.71, (1H, b), 9.31, (1H, t), 9.17, (1H, d), 8.39, (1H, dd), 8.22, (1H, s), 8.07, (1H, d), 7.83, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.29-7.25, (2H, m), 6.94, (2H, m), 6.84, (1H, d), 4.52, (2H, d), 3.75, (3H, s), 2.45, (3H, s).

6- (5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- (3-methoxybenzyl) -nicotinamide

Using general method B, 6- [5-cyclopropylmethylcarbamoyl-2-methyl-phenyl] -N- (3-methoxybenzyl) -nicotinamide is converted to 6-chloro-N- (3-methoxybenzyl) nicotinamide. (Intermediate 3) and N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate 10) Manufactured from. LCMS: retention time 3.07 min, MH ⁺ 430. _{^{NMR: δH [2 H 6]}} -DMSO 9.30, (1H, t), 9.16, (1H, d), 8.62, (1H, t), 8.36, (1H, dd), 7.94, (1H, s), 7.85, (1H, d), 7.74, (1H, d), 7.43, (1H, d), 7.27, (1H, t), 6.94-6.92, (2H, m), 6.84, (1H, d), 4.51, (2H, d), 3.75, (3H, s), 3.14, (2H, t), 2.39, (3H, s), 1.03, (1H, m), 0.43, (2H, m), 0.23, (2H, m).

6- [5- (Fura-3-ylcarbonylamino) -2-methyl-phenyl] -N- (3-methoxybenzyl) -nicotinamide

Using general method B, 6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -N- (3-methoxybenzyl) -nicotinamide is converted to 6-chloro-N- (3- Methoxybenzyl) nicotinamide (intermediate 3) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -3 Prepared from furamide (intermediate 13). LCMS: retention time 3.17 min, MH ⁺ 442. NMR: δH [ ² H ₆ ] -DMSO 9.99, (1H, s), 9.29, (1H, t), 9.15, (1H, d), 8.38, (1H, s), 8.34, (1H, dd), 7.81, (2H, m), 7.75, (1H, d), 7.67, (1H, d), 7.31-7.25, (2H, m), 7.00. (1H, s), 6.94, (2H, m), 6.84, (1H, d), 4.51, (2H, d), 3.75, (3H, s), 2.32, (3H, s).

N- (3-methoxybenzyl) -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide

Using general method B, N- (3-methoxybenzyl) -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide is converted to 6-chloro-N- (3- Methoxybenzyl) nicotinamide (intermediate 3) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene- Prepared from 3-amide (Intermediate 14). LCMS: retention time 3.27 min, MH ⁺ 458. _{^{NMR: δH [2 H 6]}} -DMSO 10.12, (1H, s), 9.29, (1H, t), 9.15, (1H, d), 8.35-8.32, (2H, m), 7.86, (1H, s ), 7.78, (1H, d), 7.68-7.65, (3H, m), 7.32-7.24, (2H, m), 6.94, (2H, m), 6.84, (2H, d), 4.51, (2H D), 3.75, (3H, s), 2.32, (3H, s).

6- (5-Cyclopropylcarbamoyl-2-methyl-phenyl) -N- (3-methylsulfonylaminobenzyl) -nicotinamide

Using general method B, 6- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -N- (3-methylsulfonylaminobenzyl) -nicotinamide was converted to 6-chloro-N- (3-methylsulfonylaminobenzyl). ) Nicotinamide (Intermediate 4) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide (Intermediate) Prepared from 8). LCMS: retention time 2.71 minutes, MH ⁺ 479. _{^{NMR: δH [2 H 6]}} -DMSO 9.33, (1H, t), 9.15, (1H, s), 8.48-8.33, (3H, m), 7.89, (1H, s), 7.81, (1H, d ), 7.73, (1H, d), 7.41, (1H, d), 7.31, (1H, t), 7.21, (1H, s), 7.10, (2H, m), 4.51, (2H, d), 2.99, (3H, s), 2.86, (1H, m), 2.38, (3H, s), 0.69, (2H, m), 0.57, (2H, m).

N- (3-Methylsulfonylaminobenzyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- (3-methylsulfonylaminobenzyl) -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide is converted to 6-chloro-N- (3 -Methylsulfonylaminobenzyl) nicotinamide (intermediate 4) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiadiazole) Prepared from 2-yl) -benzamide (Intermediate 12). LCMS: Retention time 2.80 min, MH ⁺ 523. NMR: δH [ ² H ₆ ] -DMSO 9.35, (1H, t), 9.17, (2H, m), 8.38, (1H, d), 8.26, (1H, s), 8.09, (1H, d), 7.83, (1H, d), 7.52, (1H, d), 7.31, (1H, t), 7.22, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 2.99, (3H, s), 2.46, (3H, s).

N- (3-Methylsulfonylaminobenzyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- (3-methylsulfonylaminobenzyl) -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide was converted to 6-chloro-N- (3 -Methylsulfonylaminobenzyl) nicotinamide (intermediate 4) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -N- (thiazole) Prepared from 2-yl) -benzamide (Intermediate 11). LCMS: retention time 2.96 min, MH ⁺ 522. _{^{NMR: δH [2 H 6]}} -DMSO 10.19, (2H, b), 9.35, (1H, t), 9.17, (1H, s), 8.38, (1H, dd), 8.22, (1H, s), 8.07, (1H, d), 7.84, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.31-7.28, (2H, m), 7.22, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 2.99, (3H, s), 2.45, (3H, s).

6- (5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- (3-methylsulfonylaminobenzyl) -nicotinamide

Using general method B, 6- (5-cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- (3-methylsulfonylaminobenzyl) -nicotinamide was converted to 6-chloro-N- (3-methylsulfonylamino (Benzyl) nicotinamide (Intermediate 4) and N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzamide ( Prepared from intermediate 10). LCMS: retention time 2.88 min, MH ⁺ 493. _{^{NMR: δH [2 H 6]}} -DMSO 9.34, (1H, t), 9.16, (1H, d), 8.96, (1H, b), 8.62, (1H, t), 8.35, (1H, dd), 7.94, (1H, s), 7.85, (1H, d), 7.75, (1H, d), 7.43, (1H, d), 7.31, (1H, t), 7.21, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 3.14, (2H, t), 2.99, (3H, s), 2.39, (3H, s), 1.03, (1H, m), 0.43, (2H , M), 0.23, (2H, m).

6- [5- (Fura-3-ylcarbonylamino) -2-methyl-phenyl] -N- (3-methylsulfonylaminobenzyl) -nicotinamide

Using general method B, 6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -N- (3-methylsulfonylaminobenzyl) -nicotinamide is converted to 6-chloro-N- ( 3-methylsulfonylaminobenzyl) nicotinamide (intermediate 4) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Prepared from phenyl] -3-furamide (Intermediate 13). LCMS: retention time 2.93 min, MH ⁺ 505. NMR: δH [ ² H ₆ ] -DMSO 9.99, (1H, s), 9.32, (1H, t), 9.15, (1H, d), 8.95, (1H, b), 8.38, (1H, s), 8.33, (1H, dd), 7.81, (2H, d), 7.75, (1H, d), 7.68, (1H, d), 7.33-7.30, (2H, m), 7.21, (1H, s), 7.11, (2H, m), 7.01, (1H, s), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).

N- (3-Methylsulfonylaminobenzyl) -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide

Using general method B, N- (3-methylsulfonylaminobenzyl) -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide is converted to 6-chloro-N- ( 3-methylsulfonylaminobenzyl) nicotinamide (intermediate 4) and N- [4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Prepared from phenyl] thiophene-3-amide (Intermediate 14). LCMS: Retention time 3.03 minutes, MH ⁺ 521. NMR: δH [ ² H ₆ ] -DMSO 10.12, (1H, s), 9.33, (1H, t), 9.15, (1H, s), 8.78, (1H, b), 8.36-8.32, (2H, m ), 7.86, (1H, s), 7.78, (1H, d), 7.69-7.65, (3H, m), 7.31, (2H, m), 7.21, (1H, s), 7.11, (2H, m ), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).

6- (5-Cyclopropylcarbamoyl-2-methyl-phenyl) -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide

Using general method B, 6- (5-cyclopropylcarbamoyl-2-methyl-phenyl) -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide is converted to 6-chloro-N— [2- (4-Methylpiperazin-1-ylmethyl) phenyl] nicotinamide (intermediate 5) and N-cyclopropyl-4-methyl-3- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -benzamide (Intermediate 8). LCMS: retention time 2.36 min, MH ⁺ 484. NMR: δH [ ² H ₆ ] -DMSO 11.70, (1H, b), 9.23, (1H, s), 8.50, (1H, d), 8.38, (1H, d), 8.33, (1H, d), 7.92, (1H, s), 7.83, (2H, m), 7.43, (1H, d), 7.36, (1H, t), 7.29, (1H, d), 7.11, (1H, t), 3.77, (2H, s), 2.87, (1H, m), 2.67-2.24, (11H, m), 2.13, (3H, s), 0.70, (2H, m), 0.58, (2H, m).

N- [2- (4-Methylpiperazin-1-ylmethyl) phenyl] -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using general method B, N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -6- [2-methyl-5- (thiadiazol-2-ylcarbamoyl) -phenyl] -nicotinamide is converted to 6 -Chloro-N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] nicotinamide (intermediate 5) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -N- (thiadiazol-2-yl) -benzamide (intermediate 12). LCMS: retention time 2.43 min, MH ⁺ 528. NMR: δH [ ² H ₆ ] -DMSO 13.07, (1H, b), 11.74, (1H, s), 9.26, (1H, s), 9.21, (1H, s), 8.43, (1H, d), 8.34, (1H, d), 8.29, (1H, s), 8.12, (1H, d), 7.93, (1H, d), 7.56, (1H, d), 7.36, (1H, t), 7.29, (1H, d), 7.11, (1H, t), 3.78, (2H, s), 2.67-2.26, (11H, m), 2.11 (3H, s).

N- [2- (4-Methylpiperazin-1-ylmethyl) phenyl] -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide

Using General Method B, N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -6- [2-methyl-5- (thiazol-2-ylcarbamoyl) -phenyl] -nicotinamide is converted to 6 -Chloro-N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] nicotinamide (intermediate 5) and 4-methyl-3- (4,4,5,5-tetramethyl- [1,3 , 2] Dioxaborolan-2-yl) -N- (thiazol-2-yl) -benzamide (Intermediate 11). LCMS: retention time 2.53 min, MH ⁺ 527. NMR: δH [ ² H ₆ ] -DMSO 12.73, (1H, b), 11.70, (1H, b), 9.26, (1H, d), 8.43, (1H, dd), 8.33, (1H, d), 8.25, (1H, s), 8.10, (1H, d), 7.93, (1H, d), 7.58, (1H, d), 7.54, (1H, d), 7.36, (1H, t), 7.30, (2H, m), 7.12, (1H, t), 3.78, (2H, s), 2.67-2.25, (11H, b), 2.14, (3H, s).

6- (5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide

Using general method B, 6- (5-cyclopropylmethylcarbamoyl-2-methyl-phenyl) -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide is converted to 6-chloro-N -[2- (4-Methylpiperazin-1-ylmethyl) phenyl] nicotinamide (Intermediate 5) and N-cyclopropylmethyl-4-methyl-3- (4,4,5,5-tetramethyl- [1 , 3,2] dioxaborolan-2-yl) -benzamide (intermediate 10). LCMS: retention time 2.46 min, MH ⁺ 498. NMR: δH [ ² H ₆ ] -DMSO 11.67, (1H, b), 9.24, (1H, s), 8.63, (1H, t), 8.39, (1H, d), 8.32, (1H, d), 7.97, (1H, s), 7.88-7.83, (2H, m), 7.45, (1H, d), 7.36, (1H, t), 7.30, (1H, d), 7.11, (1H, t), 3.77, (2H, s), 3.15, (2H, t), 2.70-2.21, (11H, m), 1.04, (1H, m), 0.43, (2H, m), 0.23, (2H, m).

6- [5- (Fura-3-ylcarbonylamino) -2-methyl-phenyl] -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide

Using general method B, 6- [5- (fur-3-ylcarbonylamino) -2-methyl-phenyl] -N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -nicotinamide 6-chloro-N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] nicotinamide (intermediate 5) and N- [4-methyl-3- (4,4,5,5-tetramethyl- Prepared from [1,3,2] dioxaborolan-2-yl) -phenyl] -3-furamide (Intermediate 13). LCMS: retention time 2.53 min, MH ⁺ 510. NMR: δH [ ² H ₆ ] -DMSO 11.64, (1H, b), 10.02, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.86, (1H, s), 7.80, (1H, s), 7.76, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 7.01, (1H, s), 3.77, (2H, s), 2.66-2.20, (11H, m), 2.16, (3H, s).

N- [2- (4-Methylpiperazin-1-ylmethyl) phenyl] -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide

Using general method B, N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] -6- [5- (thiophen-3-ylcarbonylamino) -2-methyl-phenyl] -nicotinamide 6-chloro-N- [2- (4-methylpiperazin-1-ylmethyl) phenyl] nicotinamide (intermediate 5) and N- [4-methyl-3- (4,4,5,5-tetramethyl- Prepared from [1,3,2] dioxaborolan-2-yl) -phenyl] thiophene-3-amide (Intermediate 14). LCMS: retention time 2.58 min, MH ⁺ 526. NMR: δH [ ² H ₆ ] -DMSO 11.64, (1H, b), 10.14, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.91, (1H, s), 7.79-7.75, (2H, m), 7.65, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 3.77, (2H, s ), 2.67-2.24, (11H, m), 2.16, (3H, m).

General Law C
6-chloronicotinamide (25 mg), N-cyclopropyl-5-fluoro-4-methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl)- Benzamide (intermediate 34, 15 mg), tetrakis (triphenylphosphino) palladium (2 mg) and aqueous sodium bicarbonate (1 M, 0.5 ml) were mixed in propan-2-ol (2 ml) and heated to reflux for 18 hours. . Propan-2-ol was distilled off and the residue was diluted with ethyl acetate / cyclohexane (1: 2). The solution was loaded onto SPE (Si, 2 g) and eluted with ethyl acetate / cyclohexane (1: 2) and then with ethyl acetate. The solvent was removed from the ethyl acetate fraction and the residue was triturated with ether to give the desired product as a white solid.

The compounds of Examples 32-44 can also be prepared using {5-[(cyclopropylamino) carbonyl] -3-fluoro-2-methylphenyl} boronic acid (intermediate 36) instead of intermediate 34. it can.

General method D
A solution of intermediate 38 (40 μmol) in DMF (0.5 ml) was treated with HATU (1.12 eq) and DIPEA (3 eq). Upon shaking, a solution formed and was added to a solution of amine (1.2-2.0 equiv) in DMF (0.5 ml). After shaking, the reaction was left at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in chloroform (1.0 ml) and loaded onto SPE (NH ₂ , 0.5 g). The product was eluted with chloroform (1.5 ml), ethyl acetate (1.5 ml) and methanol / ethyl acetate (1: 9, 1.5 ml). The solvent was distilled off from the product fraction under reduced pressure.

abbreviation
DCM: Methylene chloride
DIPEA: N, N-diisopropylethylamine
DME: Dimethoxyethane
DMF: Dimethylformamide
DMSO: Dimethyl sulfoxide
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
HOBT: 1-hydroxybenzotriazole hydrate
SPE: Bond-Elut (solid phase extraction column).

  The activity of the compounds of the invention as p38 inhibitors can be demonstrated in the following assay.

p38 kinase assay
The peptide substrate used in the p38 assay was biotin-IPTSPITTTYFFFRRR-amide. p38 protein and MEK6 protein were purified to homogeneity from the E. coli expression system. The fusion protein was tagged with glutathione-S-transferase (GST) at the N-terminus. 1.5 μM peptide and 10 mM Mg (CH ₃ CO) added to 15 μL of a mixture of 1.5 μM ATP with 0.08 μCi [g- ³³ P] ATP with or without 15 μL of an inhibitor in 6% DMSO. ₂ ) Maximal activation was obtained by incubating 20 μL of a reaction mixture of 30 nM MEK6 protein and 120 nM p38 protein in the presence of a solution of ₂ in 100 mM HEPES, pH 7.5. The control was the reaction in the presence (negative control) or absence (positive control) of 50 mM EDTA. The reaction was allowed to proceed for 60 minutes at room temperature, stopped by adding 50 μL of 250 mM EDTA, and mixed with 150 μL of streptavidin SPA beads (Amersham) at 0.5 mg / reaction. The Dynatech Microfluor white U-bottom plate was sealed and the beads were allowed to settle overnight. The plates were counted for 60 seconds with a Packard TopCount. Raw data% I = 100 × (1- (I-C2) / (C1-C2)) (where I is the background CPM, C1 is the positive control and C2 is the negative control) IC ₅₀ values were obtained by adapting to.

αP38 fluorescence polarization method αP38 was obtained in-house. The SB4777790-R ligand MgCl _2, CHAPS, and diluted with HEPES containing DTT and DMSO. It was added to the blank well of a Black NUNC 384 well plate. αP38 was added to the ligand mixture and then to the rest of the 384 well plate with controls and compounds. Plates were read with an LJL Analyst and compound inhibition was calculated using fluorescence anisotropy.

Results The compounds described in the Examples were examined according to the above method and had an IC ₅₀ value of less than 10 μM.

Claims (13)

A compound of the following formula (I):

[Where:
R ¹ is hydrogen, C _1-6 alkoxy, halogen and optionally substituted by not more than three groups selected from hydroxy C _1-6 alkyl, C _2-6 alkenyl, 1 or more C _1-6 C _3-7 cycloalkyl optionally substituted by an alkyl group, phenyl optionally substituted by up to 3 groups selected from R ⁵ and R ⁶ , and 3 selected from R ⁵ and R ⁶ Selected from heteroaryl optionally substituted by not more than one group;
R ² is selected from hydrogen, C _1-6 alkyl and — (CH ₂ ) _q —C _3-7 cycloalkyl, optionally substituted by one or more C _1-6 alkyl groups;
Alternatively, (CH ₂ ) _m R ¹ and R ² together with the nitrogen atom to which they are bonded may be substituted with 3 or less C _1-6 alkyl group and may be substituted with 4 to 6 membered complex. Forming a ring;
R ³ is chloro or methyl;
R ⁴ is a group —NH—CO—R ⁷ or —CO—NH— (CH ₂ ) _q —R ⁸ ;
R ⁵ is C _1-6 alkyl, C _1-6 alkoxy, optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , —SO ₂ NHR ⁹ , — (CH ₂ ) _s NHSO ₂ R ¹⁰ , halogen, CN, OH, — (CH ₂ ) _s NR ¹¹ R ¹² and trifluoromethyl;
R ⁶ is selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, trifluoromethyl and — (CH ₂ ) _s NR ¹¹ R ¹² ;
R ⁷ is hydrogen, C _1-6 alkyl, _optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, trifluoromethyl, R ¹³ and / or or optionally substituted by R ¹⁴ - (CH _{2) r} heteroaryl, and optionally substituted by R ¹³ and / or R ¹⁴ - (CH ₂₎ selected from the _r phenyl;
R ⁸ is substituted by hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl optionally substituted by one or more C _1-6 alkyl groups, CONHR ⁹ , R ¹³ and / or R ¹⁴ Selected from good phenyl and heteroaryl optionally substituted by R ¹³ and / or R ¹⁴ ;
R ⁹ and R ¹⁰ are each independently selected from hydrogen and C _1-6 alkyl;
Alternatively, R ⁹ and R ¹⁰ may have one further heteroatom selected from oxygen, sulfur and NR ¹⁵ together with the nitrogen atom to which they are attached. And the ring may be substituted by not more than 2 C _1-6 alkyl groups;
R ¹¹ is selected from hydrogen, C _1-6 alkyl and — (CH ₂ ) _q —C _3-7 cycloalkyl, optionally substituted by one or more C _1-6 alkyl groups;
R ¹² is selected from hydrogen and C _1-6 alkyl;
Alternatively, R ¹¹ and R ¹² together with the nitrogen atom to which they are attached may have one further heteroatom selected from oxygen, sulfur and NR ¹⁵ 5 or 6 Forming a heterocycle of members;
R ¹³ is C _1-6 alkyl, C _1-6 alkoxy, optionally substituted by one or more C _1-6 alkyl groups — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ^10, -NHCOR ^10, _{halogen, CN, - (CH 2)} s NR 11 R 12, trifluoromethyl, optionally substituted by one or more optionally substituted by R ¹⁴ groups phenyl and one or more, R ¹⁴ group Selected from optionally heteroaryl;
R ¹⁴ is selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, trifluoromethyl and —NR ¹¹ R ¹² ;
R ¹⁵ is selected from hydrogen and methyl;
X and Y are each independently selected from hydrogen, methyl and halogen;
Z is a halogen;
m is selected from 0, 1, 2, 3 and 4 and each carbon atom of the resulting carbon chain may be substituted by up to 2 groups independently selected from C _1-6 alkyl and halogen;
n is selected from 0, 1 and 2;
q is selected from 0, 1 and 2;
r is selected from 0 and 1;
s is selected from 0, 1, 2 and 3. ] 3 selected from R ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _3-7 cycloalkyl optionally substituted by one or more C _1-6 alkyl groups, R ⁵ and R ⁶ a compound according to claim 1 which is selected from heteroaryl optionally substituted by to 3 substituents selected phenyl optionally substituted from R ⁵ and R ⁶ with the following substituents. The compound according to claim 1 or ² , wherein R ² is hydrogen. The compound according to any one of claims 1 to 3, wherein R ³ is methyl.   X is fluorine, The compound in any one of Claims 1-4. R ⁷ may be substituted by C _1-6 alkyl, — (CH ₂ ) _q —C _3-7 cycloalkyl, trifluoromethyl, R ¹³ and / or R ¹⁴ — (CH ₂ ) _r heteroaryl As well as C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q —C _3-7 cycloalkyl, —CONR ⁹ R ¹⁰ , —NHCOR ¹⁰ , halogen, CN, trifluoromethyl, one or more R optionally substituted by heteroaryl optionally substituted by optionally substituted phenyl and / or one or more R ¹⁴ groups by ¹⁴ groups - (CH ₂₎ according to claim 1 which is selected from the _r phenyl 6. The compound according to any one of 5. R ⁸ is C _3-7 cycloalkyl, heteroaryl optionally substituted by CONHR ⁹ , R ¹³ and / or R ¹⁴ , and C _1-6 alkyl, C _1-6 alkoxy, — (CH ₂ ) _q -C _3-7 ^{cycloalkyl, -CONR 9 R 10, -NHCOR 10} , halogen, CN, trifluoromethyl, by one or more optionally substituted by R ¹⁴ groups phenyl and also / or one or more R ¹⁴ groups 7. A compound according to any one of claims 1 to 6 selected from phenyl optionally substituted by optionally substituted heteroaryl.   2. A compound according to claim 1 as defined in any of Examples 1 to 123.   9. A pharmaceutical composition comprising a compound according to any of claims 1-8 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.   9. A method of treating a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38 kinase in a patient in need thereof, according to any of claims 1-8. A method comprising administering a compound of:   9. A compound according to any one of claims 1-8 for use in therapy.   Use of a compound according to any of claims 1-8 in the manufacture of a medicament for use in the treatment of a condition or disease state mediated by cytokines produced by the activity of p38 kinase or by the activity of p38 kinase. A process for producing a compound of formula (I) according to any of claims 1-8,
(A) Compound of the following formula (II):

Wherein R ¹ , R ² , Z, m and n are as defined in claim 1 and W is a halogen, and a compound of formula (III):

(Wherein R ³ , R ⁴ , X and Y are as defined in claim 1) in the presence of a catalyst; or (b) a compound of formula (VIII):

Is reacted with a compound of formula (III) as defined above, and the acid so formed is then converted to an amine of formula (V):

(Wherein R ¹ , R ² and m are as defined in claim 1) and reacting under amide forming conditions; or (c) a compound of formula (II) as defined above is Compound of formula (IX):

(Wherein R ³ , R ⁴ , X and Y are as defined in claim 1) and a reaction in the presence of a catalyst.